Abstract
Insulin-producing β-cells constitute the majority of the cells in the pancreatic islets. Dysfunction of these cells is a key factor in the loss of glucose regulation that characterizes type 2 diabetes. The regulation of many of the functions of β-cells relies on their close interaction with the intra-islet microvasculature, comprised of endothelial cells and pericytes. In addition to providing islet blood supply, cells of the islet vasculature directly regulate β-cell activity through the secretion of growth factors and other molecules. These factors come from capillary mural pericytes and endothelial cells, and have been shown to promote insulin gene expression, insulin secretion, and β-cell proliferation. This review focuses on the intimate crosstalk of the vascular cells and β-cells and its role in glucose homeostasis and diabetes.
Keywords: islet vasculature, endothelial cells, pericytes, beta-cells, Islets of Langerhans, basement membrane
Introduction
Pancreatic β-cells reside in a complex microenvironment, where they interact with other endocrine cells, as well as vascular endothelial cells and pericytes, immune cells and neurons (1–4). This review focuses on the crosstalk of β-cells with vascular cells and their role in glucose homeostasis and diabetes.
Islets, comprised of highly vascularised clusters of endocrine cells, are the functional units within the pancreas that control blood sugar levels. A dense capillary network surrounds and penetrates each pancreatic islet to enable glucose sensing and insulin secretion into peripheral circulation (5–8). While representing only 1–2% of the pancreatic mass, islets receive up to 20% of the direct arterial blood flow to the pancreas (9). Structural and phenotypical analysis of the pancreatic vasculature demonstrate a dense network of thick, highly-branched capillaries within islets (1, 10) - due to this high level of vascularisation, almost all β-cells come into contact with a capillary (11, 12). Pancreatic capillary structure consists of a highly-fenestrated, luminal layer of endothelial cells (13) surrounded by pericytes, which are abluminal mural cells embedded within the microvessel basement membrane (14). While there is a large body of data surrounding the roles of endothelial cells in the function of capillary beds (15–20), the specific roles of pericytes are complex and not fully understood. However, recent studies showed that pericytes play a vital role in regulating β-cell function and mass (21–24). Both types of islet vascular cells are known to promote insulin production and secretion, as well as β-cell proliferation, survival, and maturation, by secreting a variety of growth factors, components of the extracellular matrix (ECM), and other molecules (5, 22, 23, 25–27).
β-Cells do not appear to directly contact vascular cells, instead, a double-layered basement membrane comprised of extracellular matrix (ECM) glycoproteins surrounds islet capillaries in both humans (28) and mice (29), lying between the vascular and β-cells. It is apparent that β-cells specifically respond to regional contact with the capillaries. Each β-cell is structurally polarised with a basal domain at the point of capillary contact and an apical domain positioned away from the capillaries (12, 30). Synaptic scaffold proteins are enriched in this basal domain and insulin granule fusion is selectively targeted to this region (12, 31).
Vascular cells in the islets are involved in tissue inflammation and immunoregulation. Endothelial cells recruit macrophages, which in turn induce β-cell proliferation and regeneration (5–7). Although the immunoregulatory properties of pericytes in other tissues, such as the brain (32, 33) and kidney (34), are well-established, whether pancreatic pericytes have similar capabilities in the islet have yet to be reported.
Accumulating evidence is showing that the interactions between vascular cells and β-cells are essential for correct islet development and become key factors in the regulation of adult islet function.
Role of Vascular Cells in Islet Embryonic Development
The development of many tissues, including the pancreas, depends on the interactions of various cell types. Pancreatic endocrine and exocrine cells originate from the foregut endoderm and acquire their differentiated fate in a sequential process (21–24, 35). Cells of the embryonic pancreatic microenvironment, including endothelial and mesenchymal cells, have been shown to regulate this process (24, 36).
The embryonic pancreatic mesenchyme regulates pancreas organogenesis, primarily through promoting appropriate survival and proliferation of endoderm-derived cells (37). In the final stages of embryonic development, pericytes originate from the pancreatic mesenchyme (24, 38), which stimulates the replication of differentiated β-cells (37, 38). β-Cells continue to proliferate during the neonatal stage (39), and Diphtheria Toxin-mediated depletion of neonatal pericytes results in a reduced rate of β-cells replication demonstrating the influence of pericytes on β-cell expansion in both the embryonic and neonatal pancreata (22).
Endothelial cells also play a key role in islet development. The reciprocal influences of β-cells and islet endothelial cells affect development of both the vasculature (40) and β-cells (41, 42). Evidence indicates that β-cells are unlikely to synthesize their own ECM components, and that developmental expression of angiogenic protein VEGFA from β-cells is vital to encourage the islet vascularisation required for basement membrane formation in developing islets (25, 43).
Given that the islets comprise an endocrine organ and are therefore dependent on close coupling with the whole-body blood circulation, it is not surprising that vascular cells such as pericytes and endothelial cells are important for islet development. The uncovering of the roles and mechanisms of these vascular cells is interesting and potentially important for cell-based treatments for diabetes.
Vascular Regulation of Adult Islet Function
Exactly how pericytes and endothelial cells influence β-cell function in an adult islet is a developing area of study (44) and can, in principle, occur through a variety of effects including; capillary behaviour, secreted factors, direct contact, or ECM-driven interactions.
The Role of Vascular Cells in Capillary Behaviour
Islet blood flow is obviously important for endocrine function and allows the rapid sensing of fluctuations in blood glucose and outflow of secreted hormones. It is controlled by various nutrients and growth factors (1) and, in turn, impacts on β-cell insulin secretory activity (4, 45).
Approximately 40% of islet microvasculature is covered by pericytes (21) which adjust the vascular diameter and capillary blood flow by vasoconstriction and vasodilation (46). Research in this area has identified several molecules responsible for the regulation of pericyte contractile tone. For example, pericytes in the brain have been shown to express receptors for vasoactive molecules (47). Endothelial cells are known to secrete vasoactive factors, including vasodilators nitric oxide and prostacyclin as well as vasoconstrictors thromboxane and endothelin-1 (48). In the pancreas, adenosine released during ATP breakdown increases islet blood flow (49) and relaxes pericytes to dilate islet capillaries (21). In contrast, the sympathetic neurotransmitter noradrenaline induces contraction of islet capillaries and reduces blood flow (21). The cellular contacts and paracrine signalling between endothelial cells and pericytes that regulate vascular tone likely influence blood flow effects on β-cell endocrine function.
The Role of Secreted Factors From Vascular Cells
There is now extensive evidence that pericytes directly support β-cell function and glucose homeostasis independent of blood flow (6, 22, 23, 26, 27). In vivo depletion of pericytes in the pancreas using the Diphtheria Toxin Receptor system allows study of the role in β-cell function and proliferation (22, 27). This depletion of pancreatic pericytes leads to glucose intolerance due to reduced islet insulin content and secretion, as well as diminished expression of cellular components required for β-cell functionality. Importantly, reduced levels of MafA and Pdx1, transcription factors essential for β-cell maturity, indicate β-cell de-differentiation occurs in the absence of pericytes (27). Pancreatic pericytes are further shown to secrete factors that regulate glucose-stimulated insulin secretion (GSIS). Pancreatic mural cells, i.e., pericytes and vascular smooth muscle cells, produce nerve growth factor (NGF) upon glucose stimulation (23). β-Cells express the NGF receptor tropomyosin receptor kinase A (TrkA), and the activation of this receptor promotes insulin exocytosis via glucose-induced β-cell actin remodelling (23). In humans, altered circulating NGF levels have been noted in type 2 diabetes and mutations in the TrkA gene cause decreased GSIS (50, 51). Pericytes further produce Bone morphogenetic protein 4 (BMP4), through which they potentially directly regulate β-cell function (26). While the activity of the BMP4 receptor BMPR1A is essential for proper β-cell gene expression and function (52), the involvement of pericytic BMP4 in this process was yet to be reported. The evidence of glucose-stimulated paracrine signaling between pericytes and β-cells highlights the importance of pericytes in glucose homeostasis and GSIS under physiological conditions.
Among the many factors secreted by intra-islet endothelial cells, connective tissue growth factor (CTGF) and thrombospondin (TSP)-1 have known effects on β-cells (53). CTGF, a matricellular protein active throughout the body (54), drives β-cell expansion during embryogenesis in an autocrine manner (55), thought to occur due to multiple development-related transcription factor binding sites located on the CTGF gene although a mechanism has not yet been clearly defined (56). In the adult pancreas, CTGF is expressed mostly by islet endothelial cells (57). Islets that underwent partial destruction of β-cell content were treated with CTGF, leading to a 50% mass recovery attributed to the proliferative effects of the growth hormone (58). Production of TSP-1, an anti-angiogenic protein secreted by intra-islet endothelial cells, is upregulated by elevated blood glucose levels in humans (59). TSP-1-deficiency, however, leads to pancreatic hyperplasia, glucose intolerance, and impaired GSIS (60) despite knockdown-related improvements in transplanted islet revascularization (61). Rescue of TSP-1-deficient murine islets through treatment with transforming growth factor (TGF) β-1 activation inhibits the decreased glucose tolerance (60), providing insight into potential mechanisms. However, long-term deficiency of TSP-1 results in persistent dysfunction of glucose tolerance, even in the face of compensatory normalisation of β-cell mass (62). Additional molecules produced in non-pancreatic endothelial cells, such as hepatocyte growth factor (HGF), influence β-cell function as well via exocrine signaling (63).
Direct Contacts Between Vascular Cells and β-Cells
Due to the structure of the double-layered basement membrane (28, 64), β-cells are unlikely to make direct contact with intra-islet vascular endothelial cells or pericytes. However, there are candidate proteins that might indicate direct links are possible. For example, the pre- and post-synaptic proteins neurexin and neuroligin are expressed by vascular mural and endothelial cells (65), and have additionally been identified in β-cells (66). In neurons, these binding partners directly contact each other and mediate a plethora of biological functions (67) including synaptic organisation. Over-expression of post-synaptic receptor neuroligin-2 expression in β-cells increases GSIS (68) and promotes insulin granule docking (69). The neurexin-neuroligin interactions therefore appear to be involved in regulating β-cell function. These interactions may arise through β-cell-to-β-cell contacts, but it remains an intriguing possibility that they result from interactions between the β-cells and the vascular cells. Connexins 36 and 43, which form gap junctions between cells, are similarly expressed by both endothelial and β-cells, however there is currently no evidence demonstrating direct contacts between the two cell types (44).
Interactions of β-Cells With the Basement Membrane
Various proteins of the vascular basement membrane are implicated in the regulation of β-cell function, proliferation, and expansion (22, 25, 64, 70). The basement membrane is comprised of glycoproteins including laminins, fibronectin, nidogens, and collagens (29, 71). The basement membrane surrounds the intra-islet capillaries and the islet capsule but is not present between endocrine cells (29); therefore, β-cells contact the basement membrane only in the regions which they contact the vasculature (25, 30). Evidence demonstrates that these contacts, mediated through integrin activation (31), assist in driving β-cell polarity and the targeting of insulin secretion (12, 31) in addition to modulating insulin gene expression (25), β-cell proliferation and survival (72), and GSIS functionality (73, 74).
Both endothelial and pericytes secrete ECM components that make up the islet basement membrane. Endothelial cells are responsible for the synthesis and maintenance of the ECM/basement membrane, specifically producing laminin and collagen IV (25, 75, 76). Pancreatic pericytes also produce an array of basement membrane components, including collagen IV, laminins, proteoglycans, and nidogen (77). In particular, pancreatic pericytes and endothelial cells both produce laminin α4, which promotes the expression levels of the β-cell genes Ins1, MafA, and Glut2, as well as GSIS (77).
In vitro research surrounding the function of pancreatic islets is largely performed with cells derived from isolated islets, obtained through enzymatic destruction of the ECM structure (78, 79). Although islets retain some endothelial cell expression immediately post-isolation, the endothelial cells are rapidly diminished during culture with islets losing approximately 85% of endothelial cells within two days of culture (80). This loss of vasculature negatively impacts the endocrine function of isolated islets (25). Various lines of evidence show that attempts to preserve, restore or replace the vascular cells is beneficial to β-cells. Endothelial cell-conditioned medium in culture of dispersed β-cells improves GSIS with a laminin-dependent mechanism (81). Similarly, exposure to pericyte-conditioned medium stimulates proliferation in cultured β-cells in an integrin-dependent manner (10, 22). In islet transplantation, supplementing islets with endothelial cells improves revascularisation and functional outcomes compared to islets alone (82–84).
Additionally, simple incorporation of basement membrane proteins into cell cultures has repeatedly been shown to benefit cultured β-cell function and survival and is furthermore a useful approach to gain a mechanistic understanding of the processes involved. Introduction of laminins α4 and α5 to β-cells cultured in vitro on glass increases insulin gene expression and enhances GSIS, effects that are inhibited by the blockade of the integrin β1 receptor (25). β1 integrin has been demonstrated to regulate GSIS (85) as well as β-cell expansion (70), furthering the evidence that β1 integrins play a key role in ECM influences on β-cell endocrine function.
In addition to affecting β-cell function, ECM contacts between islet vasculature and β-cells contribute to β-cell polarity (12, 30) and likely orientate the site of targeted insulin secretion to the capillaries (12, 31). Targeting of insulin granule fusion appears to be driven by the localisation of pre-synaptic scaffold proteins, including liprin, RIM2, piccolo, and ELKS, at the contact point of β-cells and the islet vasculature (12, 86) and has been shown to depend on localised β1 integrin activation (31).
Contact between β-cells and ECM triggers focal adhesion formation downstream of β1 integrin activation, shown via immunostaining to occur exclusively at the interface between islet blood vessels and β-cells (31). As insulin granule fusion is biased towards this interface (12, 31), current evidence indicates this targeting of secretion requires the focal adhesion activation and the specific involvement of focal adhesion kinase (FAK). Evidence suggests FAK as a vital signaling mediator for β-cell endocrine function, as pharmacological and genetic inhibition of FAK reduces insulin secretion (87) and disrupts secretion targeting in vitro (12, 31), while in vivo knockout of pancreas-specific FAK results in impaired GSIS and diminished glucose tolerance (88). Although the recruitment and activation of FAK appears essential for normal GSIS, further downstream pathways are currently unclear. Other kinase-associated pathways, such as the extracellular signal-related kinase (ERK), have similarly been shown to regulate GSIS (89), however further investigation into specific signaling cascades will be required to expand on the pathways responsible for modulating β-cell function.
Involvement of Islet Vascular Cells in Diabetes
Abnormalities in the islet vasculature may drive β-cell dysfunction and diabetes progression. Changes in pericyte function and mass has been implicated in obesity and diabetes (6, 7, 26, 90). Pancreatic pericytes were recently demonstrated to express the diabetes gene transcription factor 7-like 2 (TCF7l2) (26). Polymorphism in TCF7L2 (TCF4) strongly correlates with an increased risk of type 2 diabetes (91). Pericyte-specific inactivation of Tcf7l2 impairs glucose homeostasis due to aberrant insulin production and GSIS (26). This impairment has been associated with reduced expression levels of genes associated with β-cell function and maturity, including MafA, Pdx1 and NeuroD1. Furthermore, pancreatic pericytes are shown to produce secreted factors in a Tcf7l2-dependent manner that potentially support β-cell function and glucose response (26). Diabetic retinopathy is characterized by an early loss of retinal pericytes under hyperglycemic conditions (92, 93). Loss of pericytes in the liver and brain leads to endothelial hyperplasia and abnormal vascular (94, 95). In the islets, progression of type 2 diabetes is associated with and may be contributed to by a gradual loss of pericytic coverage of islet capillaries (96).
As β-cell function declines and diabetes progresses, poorly controlled blood glucose levels in the form of chronic hyperglycaemia contributes significantly to abnormal protein glycation throughout the islets and other non-pancreatic tissues (97, 98). The advanced glycation end-products (AGEs) formed by this process are implicated in both worsening β-cell function as well as in development of long-term diabetic complications including diabetic retinopathy (99, 100), nephropathy (100, 101), and decreased insulin sensitivity in adipose tissues (102). Furthermore, islets/β-cells exposed to AGEs in culture shown to have impaired GSIS and other functional defects (103, 104). Although not currently clear, effects on β-cell endocrine function may, in part, be mediated by effects on the ECM proteins of the basement membrane, which are generally long-lived proteins and therefore more susceptible to accumulating effects of glycation.
Both type 1 and type 2 diabetes have been associated ECM abnormalities: progression of type 1 diabetes-related β-cell destruction is correlated with the amount of leukocyte-induced damage to the peri-islet basement membrane (105), while type 2 diabetes islets exhibit thicker, less branched intra-islet capillaries (106) with increased fibrosis surrounding the vasculature (107). Furthermore, pancreatic pericytes can convert to myofibroblasts (96) which leads to aberrant ECM production and tissue fibrosis and would further contribute to impaired β-cell function. Specifically for AGE-related changes to ECM structure, AGE increases crosslinking of the ECM to increase stiffness (108) which may impact on the local islet environment and may inhibit cellular signaling and behaviour. Alteration in ECM stiffness is associated with dysfunction in numerous well-studied disease states, including cancer (109–111), cardiovascular disease (112), and other fibrotic diseases (113, 114). Additionally, the receptor for AGEs (RAGE) is expressed by both endothelial cells and pericytes (115). Along with AGE-triggered basement membrane modification (116), AGE receptors are thought to be involved in the triggering of retinal pericyte apoptosis that occurs in diabetic retinopathy (115) - it may be that islet pericytes undergo similar apoptotic signaling, further impacting pancreatic endocrine function.
Concluding Remarks
The islet vasculature affects various aspects of pancreatic function and GSIS through both blood flow-dependent and -independent pathways as summarized in Table 1 . While each of the vascular components, namely endothelial cell and pericytes, are known to individually support β-cell function, whether these cells have a synergistic effect are yet to be directly studied. For example, heterotypic interactions of pericytes and endothelial cells are required for vascular basement membrane assembly in many tissues but this has not yet been shown in the pancreas. Further, whether direct interactions between islet endothelial cells and pericytes affect the other’s production and secretion of factors, thus influencing their ability to support β-cells, is yet to be uncovered.
Table 1.
Feature | Endothelial cells | Pericytes |
---|---|---|
Cell markers | CD31 (117, 118) CD146, CD105 (118) nephrin (119) von Willebrand’s factor (118) |
NG2, PDGFR β (120) |
Known effects on β -cells | Gene expression (25) Insulin secretion (7) Replication (5, 25) |
Gene expression (26, 27, 77) GSIS (23, 26, 27) Replication (22) Regulation of islet blood flow (21) |
Factors secreted | Connective tissue growth factor (CTGF) (53) Thrombospondin (TSP)-1 (60) |
Nerve growth factor (NGF) (23) Bone morphogenetic protein 4 (BMP4) (26) |
Basement membrane components produced | Collagen IV Laminin α4 Laminin α5 (25) |
Collagen IV Laminin α2 Laminin α4 Nidogens Perlecans (77) |
Immunoregulatory function | Recruit pancreatic macrophages (5) | Unknown in pancreas Leukocyte trafficking/activation in brain and kidney (32–34) Production of anti-inflammatory factors (33, 121, 122) |
Implications in diabetes | Activation of AGE receptors may contribute to progressive complications (115) Alterations of vasculature in diabetic islets (107) and secreted basement membrane (106) associated with disease-related islet damage (105) and malfunction (107) |
Type 2 diabetes is associated with a reduced density (21) Support of β-cells depends on the diabetes gene TCF7L2 (26) Transform to myofibroblast during stress (96) |
Author Contributions
GB, CB, PT, and LL wrote and edited the manuscript. All authors contributed to the article and approved the submitted version.
Funding
Project funding was obtained from the National Health and Medical Research Council (APP1128273 and APP1146788; to PT), the Israel Science Foundation (ISF; Grant agreement no. 1605/18; to LL), and the European Union’s Horizon 2020 Research and Innovation Programme (Grant agreement no. 800981; to LL).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
- 1. Aamodt KI, Powers AC. Signals in the Pancreatic Islet Microenvironment Influence β-Cell Proliferation. Diabetes Obes Metab (2017) 19 Suppl 1(Suppl 1):124–36. 10.1111/dom.13031 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Almaça J, Caicedo A, Landsman L. Beta Cell Dysfunction in Diabetes: The Islet Microenvironment as an Unusual Suspect. Diabetologia (2020) 63(10):2076–85. 10.1007/s00125-020-05186-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Eberhard D, Lammert E. The Pancreatic Beta-Cell in the Islet and Organ Community. Curr Opin Genet Dev (2009) 19(5):469–75. 10.1016/j.gde.2009.07.003 [DOI] [PubMed] [Google Scholar]
- 4. Jansson L, Barbu A, Bodin B, Drott CJ, Espes D, Gao X, et al. Pancreatic Islet Blood Flow and its Measurement. Ups J Med Sci (2016) 121(2):81–95. 10.3109/03009734.2016.1164769 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Brissova M, Aamodt K, Brahmachary P, Prasad N, Hong J-Y, Dai C, et al. Islet Microenvironment, Modulated by Vascular Endothelial Growth Factor-a Signaling, Promotes β Cell Regeneration. Cell Metab (2014) 19(3):498–511. 10.1016/j.cmet.2014.02.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Hayes KL. Pericytes in Type 2 Diabetes. In: Birbrair A, editor. Pericyte Biology in Disease. Cham: Springer International Publishing; (2019). p. 265–78. 10.1007/978-3-030-16908-4_12 [DOI] [Google Scholar]
- 7. Richards OC, Raines SM, Attie AD. The Role of Blood Vessels, Endothelial Cells, and Vascular Pericytes in Insulin Secretion and Peripheral Insulin Action. Endocrine Rev (2010) 31(3):343–63. 10.1210/er.2009-0035 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Dybala MP, Kuznetsov A, Motobu M, Hendren-Santiago BK, Philipson LH, Chervonsky AV, et al. Integrated Pancreatic Blood Flow: Bidirectional Microcirculation Between Endocrine and Exocrine Pancreas. Diabetes (2020) 69(7):1439–50. 10.2337/db19-1034 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Lifson N, Lassa CV, Dixit PK. Relation Between Blood Flow and Morphology in Islet Organ of Rat Pancreas. Am J Physiol (1985) 249(1 Pt 1):E43–8. 10.1152/ajpendo.1985.249.1.E43 [DOI] [PubMed] [Google Scholar]
- 10. Chen J, Lippo L, Labella R, Tan SL, Marsden BD, Dustin ML, et al. Decreased Blood Vessel Density and Endothelial Cell Subset Dynamics During Ageing of the Endocrine System. EMBO J (2020) 40(1):e105242. 10.15252/embj.2020105242 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Bonner-Weir S, Sullivan BA, Weir GC. Human Islet Morphology Revisited: Human and Rodent Islets Are Not So Different After All. J Histochem Cytochem (2015) 63(8):604–12. 10.1369/0022155415570969 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Cottle L, Gan WJ, Gilroy I, Samra JS, Gill AJ, Loudovaris T, et al. Structural and Functional Polarisation of Human Pancreatic Beta Cells in Islets From Organ Donors With and Without Type 2 Diabetes. Diabetologia (2021) 618–29. 10.1007/s00125-020-05345-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Kolka CM, Bergman RN. The Barrier Within: Endothelial Transport of Hormones. Physiology (2012) 27(4):237–47. 10.1152/physiol.00012.2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Armulik A, Genové G, Betsholtz C. Pericytes: Developmental, Physiological, and Pathological Perspectives, Problems, and Promises. Dev Cell (2011) 21(2):193–215. 10.1016/j.devcel.2011.07.001 [DOI] [PubMed] [Google Scholar]
- 15. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Blood Vessels and Endothelial Cells. In: Biology of the Cell, 4th ed. New York: Garland Science; (2002). [Google Scholar]
- 16. Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, et al. The Vascular Endothelium and Human Diseases. Int J Biol Sci (2013) 9(10):1057–69. 10.7150/ijbs.7502 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Deanfield John E, Halcox Julian P, Rabelink Ton J. Endothelial Function and Dysfunction. Circulation (2007) 115(10):1285–95. 10.1161/CIRCULATIONAHA.106.652859 [DOI] [PubMed] [Google Scholar]
- 18. Michiels C. Endothelial Cell Functions. J Cell Physiol (2003) 196(3):430–43. 10.1002/jcp.10333 [DOI] [PubMed] [Google Scholar]
- 19. Moradipoor S, Ismail P, Etemad A, Sulaiman WAW, Ahmadloo S. Expression Profiling of Genes Related to Endothelial Cells Biology in Patients With Type 2 Diabetes and Patients With Prediabetes. BioMed Res Int (2016). 10.1155/2016/1845638 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Félétou M. Multiple Functions of the Endothelial Cells. In: . The Endothelium: Part 1: Multiple Functions of the Endothelial Cells—Focus on Endothelium-Derived Vasoactive Mediators. San Rafael (CA: Morgan & Claypool Life Sciences; (2011). 10.4199/C00031ED1V01Y201105ISP019 [DOI] [PubMed] [Google Scholar]
- 21. Almaça J, Weitz J, Rodriguez-Diaz R, Pereira E, Caicedo A. The Pericyte of the Pancreatic Islet Regulates Capillary Diameter and Local Blood Flow. Cell Metab (2018) 27(3):630–44.e4. 10.1016/j.cmet.2018.02.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Epshtein A, Rachi E, Sakhneny L, Mizrachi S, Baer D, Landsman L. Neonatal Pancreatic Pericytes Support β-Cell Proliferation. Mol Metab (2017) 6(10):1330–8. 10.1016/j.molmet.2017.07.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Houtz J, Borden P, Ceasrine A, Minichiello L, Kuruvilla R. Neurotrophin Signaling is Required for Glucose-Induced Insulin Secretion. Dev Cell (2016) 39(3):329–45. 10.1016/j.devcel.2016.10.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Sakhneny L, Khalifa-Malka L, Landsman L. Pancreas Organogenesis: Approaches to Elucidate the Role of Epithelial-Mesenchymal Interactions. Semin Cell Dev Biol (2019) 92:89–96. 10.1016/j.semcdb2018.08.012 [DOI] [PubMed] [Google Scholar]
- 25. Nikolova G, Jabs N, Konstantinova I, Domogatskaya A, Tryggvason K, Sorokin L, et al. The Vascular Basement Membrane: A Niche for Insulin Gene Expression and Beta Cell Proliferation. Dev Cell (2006) 10(3):397–405. 10.1016/j.devcel.2006.01.015 [DOI] [PubMed] [Google Scholar]
- 26. Sakhneny L, Rachi E, Epshtein A, Guez HC, Wald-Altman S, Lisnyansky M, et al. Pancreatic Pericytes Support β-Cell Function in a Tcf7l2-Dependent Manner. Diabetes (2018) 67(3):437–47. 10.2337/db17-0697 [DOI] [PubMed] [Google Scholar]
- 27. Sasson A, Rachi E, Sakhneny L, Baer D, Lisnyansky M, Epshtein A, et al. Islet Pericytes are Required for β-Cell Maturity. Diabetes (2016) 65(10):3008–14. 10.2337/db16-0365 [DOI] [PubMed] [Google Scholar]
- 28. Virtanen I, Banerjee M, Palgi J, Korsgren O, Lukinius A, Thornell LE, et al. Blood Vessels of Human Islets of Langerhans are Surrounded by a Double Basement Membrane. Diabetologia (2008) 51(7):1181–91. 10.1007/s00125-008-0997-9 [DOI] [PubMed] [Google Scholar]
- 29. Lammert E, Thorn P. The Role of the Islet Niche on Beta Cell Structure and Function. J Mol Biol (2020) 432(5):1407–18. 10.1016/j.jmb.2019.10.032 [DOI] [PubMed] [Google Scholar]
- 30. Gan WJ, Zavortink M, Ludick C, Templin R, Webb R, Webb R, et al. Cell Polarity Defines Three Distinct Domains in Pancreatic β-Cells. J Cell Sci (2017) 130(1):143–51. 10.1242/jcs.185116 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Gan WJ, Do OH, Cottle L, Ma W, Kosobrodova E, Cooper-White J, et al. Local Integrin Activation in Pancreatic β Cells Targets Insulin Secretion to the Vasculature. Cell Rep (2018) 24(11):2819–26.e3. 10.1016/j.celrep.2018.08.035 [DOI] [PubMed] [Google Scholar]
- 32. Balabanov R, Beaumont T, Dore-Duffy P. Role of Central Nervous System Microvascular Pericytes in Activation of Antigen-Primed Splenic T-Lymphocytes. J Neurosci Res (1999) 55(5):578–87. [DOI] [PubMed] [Google Scholar]
- 33. Rustenhoven J, Jansson D, Smyth LC, Dragunow M. Brain Pericytes as Mediators of Neuroinflammation. Trends Pharmacol Sci (2017) 38(3):291–304. 10.1016/j.tips.2016.12.001 [DOI] [PubMed] [Google Scholar]
- 34. Leaf IA, Nakagawa S, Johnson BG, Cha JJ, Mittelsteadt K, Guckian KM, et al. Pericyte MyD88 and IRAK4 Control Inflammatory and Fibrotic Responses to Tissue Injury. J Clin Invest (2017) 127(1):321–34. 10.1172/JCI87532 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Pan FC, Wright C. Pancreas Organogenesis: From Bud to Plexus to Gland. Dev Dyn (2011) 240(3):530–65. 10.1002/dvdy.22584 [DOI] [PubMed] [Google Scholar]
- 36. Cleaver O, Dor Y. Vascular Instruction of Pancreas Development. Development (2012) 139(16):2833–43. 10.1242/dev.065953 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Landsman L, Nijagal A, Whitchurch TJ, Vanderlaan RL, Zimmer WE, Mackenzie TC, et al. Pancreatic Mesenchyme Regulates Epithelial Organogenesis Throughout Development. PloS Biol (2011) 9(9):e1001143. 10.1371/journal.pbio.1001143 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Harari N, Sakhneny L, Khalifa-Malka L, Busch A, Hertel KJ, Hebrok M, et al. Pancreatic Pericytes Originate From the Embryonic Pancreatic Mesenchyme. Dev Biol (2019) 449(1):14–20. 10.1016/j.ydbio.2019.01.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Wang P, Fiaschi-Taesch NM, Vasavada RC, Scott DK, García-Ocaña A, Stewart AF. Diabetes Mellitus—Advances and Challenges in Human β-Cell Proliferation. Nat Rev Endocrinol (2015) 11(4):201–12. 10.1038/nrendo.2015.9 [DOI] [PubMed] [Google Scholar]
- 40. Xiong Y, Scerbo MJ, Seelig A, Volta F, Brien N, Dicker A, et al. Islet Vascularization is Regulated by Primary Endothelial Cilia Via VEGF-A-dependent Signaling. eLife (2020) 9:NA. 10.7554/eLife.56914 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Lammert E, Cleaver O, Melton D. Induction of Pancreatic Differentiation by Signals From Blood Vessels. Science (2001) 294(5542):564–7. 10.1126/science.1064344 [DOI] [PubMed] [Google Scholar]
- 42. Yoshitomi H, Zaret KS. Endothelial Cell Interactions Initiate Dorsal Pancreas Development by Selectively Inducing the Transcription Factor Ptf1a. Development (2004) 131(4):807. 10.1242/dev.00960 [DOI] [PubMed] [Google Scholar]
- 43. Reinert RB, Brissova M, Shostak A, Pan FC, Poffenberger G, Cai Q, et al. Vascular Endothelial Growth Factor-A and Islet Vascularization Are Necessary in Developing, But Not Adult, Pancreatic Islets. Diabetes (2013) 62(12):4154. 10.2337/db13-0071 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Peiris H, Bonder CS, Coates PTH, Keating DJ, Jessup CF. The β-Cell/Ec Axis: How Do Islet Cells Talk to Each Other? Diabetes (2014) 63(1):3. 10.2337/db13-0617 [DOI] [PubMed] [Google Scholar]
- 45. Dai C, Brissova M, Reinert RB, Nyman L, Liu EH, Thompson C, et al. Pancreatic Islet Vasculature Adapts to Insulin Resistance Through Dilation and Not Angiogenesis. Diabetes (2013) 62(12):4144–53. 10.2337/db12-1657 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46. Rucker HK, Wynder HJ, Thomas WE. Cellular Mechanisms of CNS Pericytes. Brain Res Bull (2000) 51(5):363–9. 10.1016/S0361-9230(99)00260-9 [DOI] [PubMed] [Google Scholar]
- 47. Winkler EA, Bell RD, Zlokovic BV. Central Nervous System Pericytes in Health and Disease. Nat Neurosci (2011) 14(11):1398–405. 10.1038/nn.2946 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48. Sandoo A, van Zanten JJCSV, Metsios GS, Carroll D, Kitas GD. The Endothelium and its Role in Regulating Vascular Tone. Open Cardiovasc Med J (2010) 4:302–12. 10.2174/1874192401004010302 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49. Carlsson PO, Olsson R, Källskog O, Bodin B, Andersson A, Jansson L. Glucose-Induced Islet Blood Flow Increase in Rats: Interaction Between Nervous and Metabolic Mediators. Am J Physiol Endocrinol Metab (2002) 283(3):E457–64. 10.1152/ajpendo.00044.2002 [DOI] [PubMed] [Google Scholar]
- 50. Bulló M, Peeraully MR, Trayhurn P, Folch J, Salas-Salvadó J. Circulating Nerve Growth Factor Levels in Relation to Obesity and the Metabolic Syndrome in Women. Eur J Endocrinol (2007) 157(3):303–10. 10.1530/EJE-06-0716 [DOI] [PubMed] [Google Scholar]
- 51. Kim HC, Cho YJ, Ahn CW, Park KS, Kim JC, Nam JS, et al. Nerve Growth Factor and Expression of its Receptors in Patients With Diabetic Neuropathy. Diabetic Med (2009) 26(12):1228–34. 10.1111/j.1464-5491.2009.02856.x [DOI] [PubMed] [Google Scholar]
- 52. Goulley J, Dahl U, Baeza N, Mishina Y, Edlund H. Bmp4-BMPR1A Signaling in Beta Cells is Required for and Augments Glucose-Stimulated Insulin Secretion. Cell Metab (2007) 5(3):207–19. 10.1016/j.cmet.2007.01.009 [DOI] [PubMed] [Google Scholar]
- 53. Hogan MF, Hull RL. The Islet Endothelial Cell: A Novel Contributor to Beta Cell Secretory Dysfunction in Diabetes. Diabetologia (2017) 60(6):952–9. 10.1007/s00125-017-4272-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54. Chen Z, Zhang N, Chu HY, Yu Y, Zhang Z-K, Zhang G, et al. Connective Tissue Growth Factor: From Molecular Understandings to Drug Discovery. Front Cell Dev Biol (2020) 8(1239). 10.3389/fcell.2020.593269 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55. Guney MA, Petersen CP, Boustani A, Duncan MR, Gunasekaran U, Menon R, et al. Connective Tissue Growth Factor Acts Within Both Endothelial Cells and β Cells to Promote Proliferation of Developing β Cells. Proc Natl Acad Sci (2011) 108(37):15242–7. 10.1073/pnas.1100072108 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56. Charrier A, Brigstock DR. Regulation of Pancreatic Function by Connective Tissue Growth Factor (CTGF, CCN2). Cytokine Growth Factor Rev (2013) 24(1):59–68. 10.1016/j.cytogfr.2012.07.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57. Crawford LA, Guney MA, Oh YA, Deyoung RA, Valenzuela DM, Murphy AJ, et al. Connective Tissue Growth Factor (CTGF) Inactivation Leads to Defects in Islet Cell Lineage Allocation and Beta-Cell Proliferation During Embryogenesis. Mol Endocrinol (2009) 23(3):324–36. 10.1210/me.2008-0045 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58. Riley KG, Pasek RC, Maulis MF, Peek J, Thorel F, Brigstock DR, et al. Connective Tissue Growth Factor Modulates Adult β-Cell Maturity and Proliferation to Promote β-Cell Regeneration in Mice. Diabetes (2015) 64(4):1284–98. 10.2337/db14-1195 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59. Dubois S, Madec AM, Mesnier A, Armanet M, Chikh K, Berney T, et al. Glucose Inhibits Angiogenesis of Isolated Human Pancreatic Islets. J Mol Endocrinol (2010) 45(2):99–105. 10.1677/JME-10-0020 [DOI] [PubMed] [Google Scholar]
- 60. Olerud J, Mokhtari D, Johansson M, Christoffersson G, Lawler J, Welsh N, et al. Thrombospondin-1: An Islet Endothelial Cell Signal of Importance for β-Cell Function. Diabetes (2011) 60(7):1946–54. 10.2337/db10-0277 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61. Olerud J, Johansson M, Lawler J, Welsh N, Carlsson P-O. Improved Vascular Engraftment and Graft Function After Inhibition of the Angiostatic Factor Thrombospondin-1 in Mouse Pancreatic Islets. Diabetes (2008) 57(7):1870. 10.2337/db07-0724 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Drott CJ, Olerud J, Emanuelsson H, Christoffersson G, Carlsson P-O. Sustained Beta-Cell Dysfunction But Normalized Islet Mass in Aged Thrombospondin-1 Deficient Mice. PloS One (2012) 7(10):e47451–e. 10.1371/journal.pone.0047451 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63. Oliveira AG, Araújo TG, Carvalho B, Rocha GZ, Santos A, Saad MJA. The Role of Hepatocyte Growth Factor (HGF) in Insulin Resistance and Diabetes. Front Endocrinol (Lausanne) (2018) 9:503–. 10.3389/fendo.2018.00503 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64. Lammert E, Kragl M. Basement Membrane in Pancreatic Islet Function. In: Islam MS, editor. Islets of Langerhans. Dordrecht: Springer Netherlands; (2015). p. 39–58. 10.1007/978-94-007-6686-0_8 [DOI] [Google Scholar]
- 65. Bottos A, Destro E, Rissone A, Graziano S, Cordara G, Assenzio B, et al. The Synaptic Proteins Neurexins and Neuroligins are Widely Expressed in the Vascular System and Contribute to its Functions. Proc Natl Acad Sci United States America (2009) 106(49):20782–7. 10.1073/pnas.0809510106 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66. Mosedale M, Egodage S, Calma RC, Chi N-W, Chessler SD. Neurexin-1α Contributes to Insulin-Containing Secretory Granule Docking. J Biol Chem (2012) 287(9):6350–61. 10.1074/jbc.M111.299081 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67. Munder A, Israel LL, Kahremany S, Ben-Shabat-Binyamini R, Zhang C, Kolitz-Domb M, et al. Mimicking Neuroligin-2 Functions in β-Cells by Functionalized Nanoparticles as a Novel Approach for Antidiabetic Therapy. ACS Appl Mater Interfaces (2017) 9(2):1189–206. 10.1021/acsami.6b10568 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68. Suckow AT, Comoletti D, Waldrop MA, Mosedale M, Egodage S, Taylor P, et al. Expression of Neurexin, Neuroligin, and Their Cytoplasmic Binding Partners in the Pancreatic Beta-Cells and the Involvement of Neuroligin in Insulin Secretion. Endocrinology (2008) 149(12):6006–17. 10.1210/en.2008-0274 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69. Zhang C, Suckow AT, Chessler SD. Altered Pancreatic Islet Function and Morphology in Mice Lacking the Beta-cell Surface Protein Neuroligin-2. PloS One (2013) 8(6):e65711–e. 10.1371/journal.pone.0065711 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70. Diaferia GR, Jimenez-Caliani AJ, Ranjitkar P, Yang W, Hardiman G, Rhodes CJ, et al. β1 Integrin is a Crucial Regulator of Pancreatic β-Cell Expansion. Development (2013) 140(16):3360–72. 10.1242/dev.098533 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71. Ma F, Tremmel DM, Li Z, Lietz CB, Sackett SD, Odorico JS, et al. In Depth Quantification of Extracellular Matrix Proteins From Human Pancreas. J Proteome Res (2019) 18(8):3156–65. 10.1021/acs.jproteome.9b00241 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72. Kilkenny DM, Rocheleau JV. Fibroblast Growth Factor Receptor-1 Signaling in Pancreatic Islet Beta-Cells is Modulated by the Extracellular Matrix. Mol Endocrinol (Baltimore Md) (2008) 22(1):196–205. 10.1210/me.2007-0241 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73. Halban PA, Wollheim CB, Blondel B, Meda P, Niesor EN, Mintz DH. The Possible Importance of Contact Between Pancreatic Islet Cells for the Control of Insulin Release*. Endocrinology (1982) 111(1):86–94. 10.1210/endo-111-1-86 [DOI] [PubMed] [Google Scholar]
- 74. Kaido T, Yebra M, Cirulli V, Rhodes C, Diaferia G, Montgomery AM. Impact of Defined Matrix Interactions on Insulin Production by Cultured Human β-Cells. Diabetes (2006) 55(10):2723. 10.2337/db06-0120 [DOI] [PubMed] [Google Scholar]
- 75. Kusuma S, Zhao S, Gerecht S. The Extracellular Matrix is a Novel Attribute of Endothelial Progenitors and of Hypoxic Mature Endothelial Cells. FASEB J (2012) 26(12):4925–36. 10.1096/fj.12-209296 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76. Vartanian KB, Kirkpatrick SJ, McCarty OJ, Vu TQ, Hanson SR, Hinds MT. Distinct Extracellular Matrix Microenvironments of Progenitor and Carotid Endothelial Cells. J BioMed Mater Res A (2009) 91(2):528–39. 10.1002/jbm.a.32225 [DOI] [PubMed] [Google Scholar]
- 77. Sakhneny L, Epshtein A, Landsman L. Pericytes Contribute to the Islet Basement Membranes to Promote Beta-Cell Gene Expression. Sci Rep (2021) 11(1):2378. 10.1038/s41598-021-81774-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78. Villarreal D, Pradhan G, Wu C-S, Allred CD, Guo S, Sun Y. A Simple High Efficiency Protocol for Pancreatic Islet Isolation From Mice. JoVE 2019(150):e57048. 10.3791/57048 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79. Ng NHJ, Tan WX, Koh YX, Teo A. Human Islet Isolation and Distribution Efforts for Clinical and Basic Research. OBM Transplant (2019) 3:1–. 10.21926/obm.transplant.1902068 [DOI] [Google Scholar]
- 80. Nyqvist D, Köhler M, Wahlstedt H, Berggren P-O. Donor Islet Endothelial Cells Participate in Formation of Functional Vessels Within Pancreatic Islet Grafts. Diabetes (2005) 54(8):2287. 10.2337/diabetes.54.8.2287 [DOI] [PubMed] [Google Scholar]
- 81. Johansson A, Lau J, Sandberg M, Borg LA, Magnusson PU, Carlsson PO. Endothelial Cell Signalling Supports Pancreatic Beta Cell Function in the Rat. Diabetologia (2009) 52(11):2385–94. 10.1007/s00125-009-1485-6 [DOI] [PubMed] [Google Scholar]
- 82. Kang S, Park HS, Jo A, Hong SH, Lee HN, Lee YY, et al. Endothelial Progenitor Cell Cotransplantation Enhances Islet Engraftment by Rapid Revascularization. Diabetes (2012) 61(4):866. 10.2337/db10-1492 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83. Oh BJ, Oh SH, Jin SM, Suh S, Bae JC, Park C-G, et al. Co-Transplantation of Bone Marrow-Derived Endothelial Progenitor Cells Improves Revascularization and Organization in Islet Grafts. Am J Transplant (2013) 13(6):1429–40. 10.1111/ajt.12222 [DOI] [PubMed] [Google Scholar]
- 84. Penko D, Rojas-Canales D, Mohanasundaram D, Peiris HS, Sun WY, Drogemuller CJ, et al. Endothelial Progenitor Cells Enhance Islet Engraftment, Influence β-Cell Function, and Modulate Islet Connexin 36 Expression. Cell Transplant (2015) 24(1):37–48. 10.3727/096368913X673423 [DOI] [PubMed] [Google Scholar]
- 85. Riopel M, Krishnamurthy M, Li J, Liu S, Leask A, Wang R. Conditional β1-Integrin-Deficient Mice Display Impaired Pancreatic β Cell Function. J Pathol (2011) 224(1):45–55. 10.1002/path.2849 [DOI] [PubMed] [Google Scholar]
- 86. Low JT, Zavortink M, Mitchell JM, Gan WJ, Do OH, Schwiening CJ, et al. Insulin Secretion From Beta Cells in Intact Mouse Islets is Targeted Towards the Vasculature. Diabetologia (2014) 57(8):1655–63. 10.1007/s00125-014-3252-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87. Rondas D, Tomas A, Halban PA. Focal Adhesion Remodeling is Crucial for Glucose-Stimulated Insulin Secretion and Involves Activation of Focal Adhesion Kinase and Paxillin. Diabetes (2011) 60(4):1146–57. 10.2337/db10-0946 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88. Cai EP, Casimir M, Schroer SA, Luk CT, Shi SY, Choi D, et al. In Vivo Role of Focal Adhesion Kinase in Regulating Pancreatic β-Cell Mass and Function Through Insulin Signaling, Actin Dynamics, and Granule Trafficking. Diabetes (2012) 61(7):1708–18. 10.2337/db11-1344 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89. Longuet C, Broca C, Costes S, Hani EH, Bataille D, Dalle SP. Extracellularly Regulated Kinases 1/2 (P44/42 Mitogen-Activated Protein Kinases) Phosphorylate Synapsin I and Regulate Insulin Secretion in the MIN6 β-Cell Line and Islets of Langerhans. Endocrinology (2005) 146(2):643–54. 10.1210/en.2004-0841 [DOI] [PubMed] [Google Scholar]
- 90. Mahdi T, Hänzelmann S, Salehi A, Muhammed SJ, Reinbothe TM, Tang Y, et al. Secreted Frizzled-Related Protein 4 Reduces Insulin Secretion and is Overexpressed in Type 2 Diabetes. Cell Metab (2012) 16(5):625–33. 10.1016/j.cmet.2012.10.009 [DOI] [PubMed] [Google Scholar]
- 91. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, et al. Variant of Transcription Factor 7-Like 2 (TCF7L2) Gene Confers Risk of Type 2 Diabetes. Nat Genet (2006) 38(3):320–3. 10.1038/ng1732 [DOI] [PubMed] [Google Scholar]
- 92. Bergers G, Song S. The Role of Pericytes in Blood-Vessel Formation and Maintenance. Neuro Oncol (2005) 7(4):452–64. 10.1215/S1152851705000232 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93. Tu Z, Li Y, Smith DS, Sheibani N, Huang S, Kern T, et al. Retinal Pericytes Inhibit Activated T Cell Proliferation. Invest Ophthalmol Vis Sci (2011) 52(12):9005–10. 10.1167/iovs.11-8008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94. Hellström M, Gerhardt H, Kalén M, Li X, Eriksson U, Wolburg H, et al. Lack of Pericytes Leads to Endothelial Hyperplasia and Abnormal Vascular Morphogenesis. J Cell Biol (2001) 153(3):543–54. 10.1083/jcb.153.3.543 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95. Raines SM, Richards OC, Schneider LR, Schueler KL, Rabaglia ME, Oler AT, et al. Loss of PDGF-B Activity Increases Hepatic Vascular Permeability and Enhances Insulin Sensitivity. Am J Physiol Endocrinol Metab (2011) 301(3):E517–26. 10.1152/ajpendo.00241.2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96. Mateus Gonçalves L, Pereira E, Werneck de Castro JP, Bernal-Mizrachi E, Almaça J. Islet Pericytes Convert Into Profibrotic Myofibroblasts in a Mouse Model of Islet Vascular Fibrosis. Diabetologia (2020) 63(8):1564–75. 10.1007/s00125-020-05168-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97. Nowotny K, Jung T, Höhn A, Weber D, Grune T. Advanced Glycation End Products and Oxidative Stress in Type 2 Diabetes Mellitus. Biomolecules (2015) 5(1):194–222. 10.3390/biom5010194 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98. Strieder-Barboza C, Baker NA, Flesher CG, Karmakar M, Neeley CK, Polsinelli D, et al. Advanced Glycation End-Products Regulate Extracellular Matrix-Adipocyte Metabolic Crosstalk in Diabetes. Sci Rep (2019) 9(1):19748. 10.1038/s41598-019-56242-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99. Chen M, Curtis TM, Stitt AW. Advanced Glycation End Products and Diabetic Retinopathy. Curr Med Chem (2013) 20(26):3234–40. 10.2174/09298673113209990025 [DOI] [PubMed] [Google Scholar]
- 100. Genuth S, Sun W, Cleary P, Sell DR, Dahms W, Malone J, et al. Glycation and Carboxymethyllysine Levels in Skin Collagen Predict the Risk of Future 10-Year Progression of Diabetic Retinopathy and Nephropathy in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications Participants With Type 1 Diabetes. Diabetes (2005) 54(11):3103–11. 10.2337/diabetes.54.11.3103 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 101. Suzuki D, Toyoda M, Yamamoto N, Miyauchi M, Katoh M, Kimura M, et al. Relationship Between the Expression of Advanced Glycation End-Products (AGE) and the Receptor for AGE (Rage) mRNA in Diabetic Nephropathy. Intern Med (2006) 45(7):435–41. 10.2169/internalmedicine.45.1557 [DOI] [PubMed] [Google Scholar]
- 102. Unoki H, Bujo H, Yamagishi S, Takeuchi M, Imaizumi T, Saito Y. Advanced Glycation End Products Attenuate Cellular Insulin Sensitivity by Increasing the Generation of Intracellular Reactive Oxygen Species in Adipocytes. Diabetes Res Clin Pract (2007) 76(2):236–44. 10.1016/j.diabres.2006.09.016 [DOI] [PubMed] [Google Scholar]
- 103. Coughlan MT, Yap FYT, Tong DCK, Andrikopoulos S, Gasser A, Thallas-Bonke V, et al. Advanced Glycation End Products are Direct Modulators of [Beta]-Cell Function. Diabetes (2011) 60(10):2523–32. 10.2337/db10-1033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104. Lin N, Zhang H, Su Q. Advanced Glycation End-Products Induce Injury to Pancreatic Beta Cells Through Oxidative Stress. Diabetes Metab (2012) 38(3):250–7. 10.1016/j.diabet.2012.01.003 [DOI] [PubMed] [Google Scholar]
- 105. Bogdani M, Korpos E, Simeonovic CJ, Parish CR, Sorokin L, Wight TN. Extracellular Matrix Components in the Pathogenesis of Type 1 Diabetes. Curr Diabetes Rep (2014) 14(12):552. 10.1007/s11892-014-0552-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106. Brissova M, Shostak A, Fligner CL, Revetta FL, Washington MK, Powers AC, et al. Human Islets Have Fewer Blood Vessels Than Mouse Islets and the Density of Islet Vascular Structures is Increased in Type 2 Diabetes. J Histochem Cytochem (2015) 63(8):637–45. 10.1369/0022155415573324 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107. Hayden MR, Patel K, Habibi J, Gupta D, Tekwani SS, Whaley-Connell A, et al. Attenuation of Endocrine-Exocrine Pancreatic Communication in Type 2 Diabetes: Pancreatic Extracellular Matrix Ultrastructural Abnormalities. J Cardiometab Syndr (2008) 3(4):234–43. 10.1111/j.1559-4572.2008.00024.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108. Sant S, Wang D, Agarwal R, Dillender S, Ferrell N. Glycation Alters the Mechanical Behavior of Kidney Extracellular Matrix. Matrix Biol Plus (2020) 8:100035. 10.1016/j.mbplus.2020.100035 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109. Bordeleau F, Mason B, Lollis E, Mazzola M, Zanotelli M, Somasegar S, et al. Matrix Stiffening Promotes a Tumor Vasculature Phenotype. Proc Natl Acad Sci (2016) 114:201613855. 10.1073/pnas.1613855114 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110. Cox TR, Erler JT. Remodeling and Homeostasis of the Extracellular Matrix: Implications for Fibrotic Diseases and Cancer. Dis Models Mech (2011) 4(2):165. 10.1242/dmm.004077 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111. Lu P, Weaver VM, Werb Z. The Extracellular Matrix: A Dynamic Niche in Cancer Progression. J Cell Biol (2012) 196(4):395–406. 10.1083/jcb.201102147 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112. Hegab Z, Gibbons S, Neyses L, Mamas MA. Role of Advanced Glycation End Products in Cardiovascular Disease. World J Cardiol (2012) 4(4):90–102. 10.4330/wjc.v4.i4.90 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113. Hewlett JC, Kropski JA, Blackwell TS. Idiopathic Pulmonary Fibrosis: Epithelial-mesenchymal Interactions and Emerging Therapeutic Targets. Matrix Biol (2018) 71-72:112–27. 10.1016/j.matbio.2018.03.021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114. Pakshir P, Hinz B. The Big Five in Fibrosis: Macrophages, Myofibroblasts, Matrix, Mechanics, and Miscommunication. Matrix Biol (2018) 68-69:81–93. 10.1016/j.matbio.2018.01.019 [DOI] [PubMed] [Google Scholar]
- 115. Chibber R, Molinatti PA, Rosatto N, Lambourne B, Kohner EM. Toxic Action of Advanced Glycation End Products on Cultured Retinal Capillary Pericytes and Endothelial Cells: Relevance to Diabetic Retinopathy. Diabetologia (1997) 40(2):156–64. 10.1007/s001250050657 [DOI] [PubMed] [Google Scholar]
- 116. Nagaraj RH, Oya-Ito T, Bhat M, Liu B. Dicarbonyl Stress and Apoptosis of Vascular Cells: Prevention by Alphab-Crystallin. Ann N Y Acad Sci (2005) 1043:158–65. 10.1196/annals.1333.020 [DOI] [PubMed] [Google Scholar]
- 117. Albelda SM, Oliver PD, Romer LH, Buck CA. EndoCAM: A Novel Endothelial Cell-Cell Adhesion Molecule. J Cell Biol (1990) 110(4):1227–37. 10.1083/jcb.110.4.1227 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118. Favaro E, Bottelli A, Lozanoska-Ochser B, Ferioli E, Huang GC, Klein N, et al. Primary and Immortalised Human Pancreatic Islet Endothelial Cells: Phenotypic and Immunological Characterisation. Diabetologia (2005) 48(12):2552–62. 10.1007/s00125-005-0008-3 [DOI] [PubMed] [Google Scholar]
- 119. Zanone MM, Favaro E, Doublier S, Lozanoska-Ochser B, Deregibus MC, Greening J, et al. Expression of Nephrin by Human Pancreatic Islet Endothelial Cells. Diabetologia (2005) 48(9):1789–97. 10.1007/s00125-005-1865-5 [DOI] [PubMed] [Google Scholar]
- 120. Armulik A, Abramsson A, Betsholtz C. Endothelial/Pericyte Interactions. Circ Res (2005) 97(6):512–23. 10.1161/01.RES.0000182903.16652.d7 [DOI] [PubMed] [Google Scholar]
- 121. Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, et al. Il-33 Ameliorates Alzheimer’s Disease-Like Pathology and Cognitive Decline. Proc Natl Acad Sci USA (2016) 113(19):E2705–13. 10.1073/pnas.1604032113 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122. Yang Y, Andersson P, Hosaka K, Zhang Y, Cao R, Iwamoto H, et al. The PDGF-BB-SOX7 Axis-Modulated IL-33 in Pericytes and Stromal Cells Promotes Metastasis Through Tumour-Associated Macrophages. Nat Commun (2016) 7(1):11385. 10.1038/ncomms11385 [DOI] [PMC free article] [PubMed] [Google Scholar]