Table1.
Recent reports identified new evidence to support the model that endothelial cells have innate immune functions in metabolic diseases. (Part I)
| Innate immune relevance | Associated metabolic situlations | Target and experimental model | Responses on ECs | Interaction between ECs and other cells | Reference |
|---|---|---|---|---|---|
| Complement system | Early ischemia Late ischemia |
MBL (mannose-binding lectin)-deposition (MBL−/− mice) | Induces the binding of IL-1α with IL-1R1 Increases C3b and induces ICAM-1 |
10 | |
| Atherogenesis | RGC-32 (response gene to complement 32) in resident in vascular cells, but not macrophage (RGC-32−/− mice) | induces ICAM-1, VCAM-1 through directly interacting with NF-KB | RGC-32 deficiency decreases TNF-α-induced monocyte-endothelial cell interaction | 196 | |
| Reguatlion Of cytokines, chemokines and adipokines | Diabetic macular edema | BMP9/Alk1 (activin-like kinase receptor type I) (HUVECs and streptozotocin-induced mice) | Prevents VEGF-induced phosphorylation of VE-cadherin, induces occludin and strengthens vascular barrier functions | 9 | |
| Angiogenesis | BDNF (brain-derived neurotrophic factor) /NT-3 (neurotrophin-3) (ESCs, embryonic stem cells) | Promotes ESCs differentiation to ECs in a BDNF/NT3 receptors dependent way | 197 | ||
| Abdominal aortic aneurysm (AAA) | FAM3D (Mouse Models of AAA, and FAM3D−/− mice) | FAM3D is upregulated in ECs by vascular pathogenic stimuli | Contributes to neutrophil recruitment via FPR-Gi Protein/β-Arrestin-Mac-1 Signaling | 198 | |
| Atherogenesis | IL-35 (HAECs and APOE−/− mice) | Inhibits mtROS-H3K14 acetylation-activator protein 1-mediated EC activation | 199 | ||
| Vascualr inflammation | NOTCH1 signaling (HUVECs and RbpjiΔEC, NICD (Notch intracellular domain)iEC-OE mice) | Modulates the transcriptional response to inflammatory cytokines; Supports the expression of a subset of inflammatory genes at the enhancer level | Increases leukocyte recruitment to the inflamed lesion | 200 | |
| Endothelial regeneration | Cytokine-like protein dikkopf-3 (DKK3) (Human embryonic lung fibroblasts) | Drives human fibroblasts to differentiate to functional ECs via mesenchymal-to-epithelial transition and VEGF-microRNA-Stat3 pathways | 201 | ||
| Atherosclerosis and arterial stiffness | SFRP5 (secreted frizzled-related protein 5) (HUVECs, HAECs and patients with type 2 diabetes) | Restors Wnt5 (wingless-type family member 5a)-reduced NO production via eNOS | 202 | ||
| Part II | |||||
| Innate immune relevance | Associated metabolic situlations | Target and experimental model | Responses on ECs | Interaction between ECs and other cells | Reference |
| Receptor systems sensing (DMAPs) | Erosion-associated thrombosis | Neutrophil extracellular traps (HSVECs (human saphenous vein ECs) or HUVECs) | Augments ICAM-1, VCAM-1 and transcription factors through concerted action of IL-1α and cathepsin G, but not IL-1β | 11 | |
| Angiogenesis | Posttranslational proteolytic cleavage of VEGF receptors (HUVECs) | Upregulates neuropilin-1 (NRP1) species in an ADAM(a disintegrin and metalloproteinase)9/10-dependent manner resulting in inhibition of VEGF-induced EC motility and angiogenesis | 203 | ||
| Angiogenesis | MicroRNA-199a-3p/5p (bovine aortic endothelial cells) | Redundantly decreases eNOS activity and induces its degradation, thereby supporting VEGF-induced endothelial tubulogenesis | 97 | ||
| Atherogenesis | Dislipidemia and disturbed flow (HAECs and CD36−/− mice) | Increases oxLDL uptake and enhences endothelial stiffening via CD36 | 204 | ||
| Thrombophilia | Hypoxic trophoblasts derived HMGB1 (HUVECs and Pregnant mice) | Stimulates the generation and release of EC-oringin microparticles and enhances blood coagulation | Triggers neutrophil activation | 205 | |
| Thrombotic and inflammatory disorders | PolyP70 (Inorganic polyphosphate 70) (HUVECs) | Amplified HMGB1-mediated VWF release via binding to RAGE and P2Y1 receptors | Promotes VWF-platelet string formation on ECs | 15 | |
| Flow-dependent vascular remodeling | Lack of cystathionine γ-lyase (CSE−/− mice) | limits disturbed flow-induced ICAM-1, VCAM-1 through altering NO availability | Decreases monocyte infiltration | 206 | |
| Pulmonary Hypertension (PH) | HIMF Signaling (human pulmonary microvascular ECs and pulmonary arteries of patients with idiopathic PH and PH Models in mice and rats) | Triggers the HMGB1 pathway and RAGE | EC-derived HMGB1 induces an autophagic response, BMPR2 defects, and subsequent apoptosis-resistant proliferation in smooth muscle cells | 126 | |
| Pulmonary Hypertension | EC-specific caveolin-1 (Cav-1) depletion (EC-Cav1−/− mice) | exhibits a non-EC phenotype and contributes to vascular remodeling via TGF-β/pSmad2/3 signaling | With Increasing Cav-1+ extracellular vesicle shedding into the circulation and decreasing circulating monocytes | 207 | |
| Pulmonary Hypertension | Cigarette Smoke Exposure (PAECs and rats model) | Increases endothelial extracellular vesicles (eEV) generation and the spermine content in eEV | Triggers eEV migration into SMCs, and contributes to pulmonary artery smooth muscle constriction and proliferation via CaSR | 208 | |
| Vascular aging and acute myocardial infarction (AMI) | Switch in Lamb2 to Lamb1 (HUVECs and Mouse models of AMI) | Impaires the functional properties and phenotype of endothelial cell via integrin receptors | 209 | ||
| ECs Dysfunction | Nine flavors added to tobacco products (HEACs) | Iimpairs eNOS agonist-stimulated NO production and triggers inflammation, even cell death, such as vanillin and eugenol. | 5 | ||
| ECs Dysfunction | Exposure to fine particulate matter (PM2.5) (Endothelial progenitor cells, EPCs) | Impairs EPC abundance and function and prevents EPC-mediated vascular recovery after hindlimb ischemia via vascular VEGF resistance and a decrement in NO bioavailability | 210 | ||
| Hypertension | GLP-1 (glucagon-like peptide-1) analogs (Global, EC-and myelomonocytic-specific Glp1r −/− mice) | Reduces blood pressure and protects endothelial function through endothelial but not myeloid cell GLP-1 receptor | Prevents Ly6G−Ly6C+ and Ly6G+ Ly6C+ cell infiltration to the vessel wall | 211 | |
| Part III | |||||
| Innate immune relevance | Associated metabolic situlations | Target and experimental model | Responses on ECs | Interaction between ECs and other cells | Reference |
| Receptor systems sensing (HAMPs) | Organ specificity | Cardiac ECs (transcriptome) | Highly expresses key regulators in fatty acid uptake, such as Meox2/Tcf15, Fabp4, and Cd36 | 212 | |
| Pathological angiogenesis | EC-specific Atg5 deletion (HUVECs, HRMECs (human retinal microvascular ECs), MLECs (murine lung ECs) and Mice with EC-specific inactivation of Atg5) | Impairs mitochondrial function, diminishes production of mtROS, decreased oxidative inactivation of PTPs (phospho-tyrosine phosphatases)and hence, decreasing phosphorylation of the VEGFR2 | 167 | ||
| Atherogenesis | Atheroprotective pulsatile shear stress (HUVECs) | Activates ITPR3 transcription via KLF4-regulated H3K27ac (acetylation of histone 3 lysine 27) enrichment and chromatin accessibility, contributes to the Ca2+ - dependent eNOS activation and EC homeostasis. | 168 | ||
| Atherogenesis and CAD (coronary artery disease) | JCAD, CAD-associated variants at 10p11.23, knockdown (HUVECs) | Decreases ICAM-1, VCAM-1 and Selectin E by negatively regulates YAP activity and Hippo signaling | Reduces monocyte adhesion | 26 | |
| Abdominal aortic aneurysm | Cilostazol, a selective inhibitor of phosphodiesterase III (PDEIII) (MAECs and APOE−/− mice) | Reduces MCP-1 and ICAM-1 via increasing intracellular cAMP | Reduces medial disruption and macrophage infiltration in angiotensin II-Induced AAA, but no effect on atherosclerosis | 213 | |
| Pulmonary hypertension | Hypoxia (HPMEC) | Induces SENP1 (sentrin-specific protease 1)and deprivates KLF15 by SUMOylation, lossing repression on arginase 2 promoter and impairing NO production | 169 | ||
| Inflammation/Stress | A shift from AIP1A to AIP1B isoform (HUVECs) | Localizes to the mitochondria and augments TNFα-induced mtROS generation and EC activation | 170 | ||
| Hypertension | Knockdown of SIRT3 (sirtuin 3) (EPCs) | Contributes to the decline in reendothelialization capacity | Results in mitochondrial oxidative damage, hyperacetylation of SOD2 (superoxide dismutase 2) in EPCs | 171 |