Table 3.
Most recent pivotal studies on vascular dysfunction and identifying the role of AMP-activated protein kinase, potassium channels, bone morphogenetic protein 4 and P2Y2 receptor. The references represent the progression in the text according to those reported in the PRISMA flowchart.
| First Author/Year Ref | Type of Study | Cohort | Aims | Findings |
|---|---|---|---|---|
| Seki et al. 2017 J Am Heart Assoc [67] |
Rat Model | SHRs with LCZ696 or valsartan Vs SHRs without LCZ696 or valsartan Vs WK |
Wheter Angiotensin II receptor-neprilysin inhibitor sacubitril/valsartan. (LCZ696) would improve reduced EDH-mediated responses. | LCZ696 is effective as valsartan in improving the impaired EDH-mediated responses during hypertension. LCZ696 and valsartan exert beneficial effects on endothelium-independent relaxation by the ATP-sensitive K+ channel. |
| Jin et al. 2021 Sci Rep [71] |
Rat model | HPH rats in vivo PMVEC in vitro |
Whether CTRP9 has protective roles in the development of HPH. | CTRP9 lead to NO production and reduces ET-1 production by regulating AMPK activation. CTRP9 could be a target for HPH. |
| Omura et al. 2016 Circ Res. 2016 [75] |
Mice model | eAMPK (−/−) eAMPK(flox/flox) |
To determine the role of endothelial AMPK in the development of PAH. | Novel therapeutic target for the treatment of PAH exerted by endothelial AMPK. |
| Shentu et al. 2016 Arterioscler Thromb Vasc Biol [80] |
Human model Mice model |
Human umbilical vein ECs EC-specific AMPKα2 |
Whether AMPK and SIRT1 coregulate cortactin dynamics in response to shear stress. | AMPK/SIRT1 coregulated cortactin-F-actin dynamics is required for endothelial nitric oxide synthase. Atheroprotective role of AMPK/SIRT1. |
| Li et al. 2016 Arterioscler Thromb Vasc [82] |
Mice model | db/db mice Infusion miR-34a inhibitor Genetic ablation of endothelial miR-34a |
Role of endothelial miR-34a in diabetic vascular dysfunction by targeting Sirt1. | Endothelial upregulation of miR-34a leads to endothelial dysfunction by targeting Sirt1. |
| Stott et al. 2018 [85] Arterioscler Thromb Vasc |
Rat model | RA vs. MA | The role of Kv7 channels in EPAC dependent relaxations of the rat vasculature. | EPAC-dependent vasorelaxations occur in part via activation of Kv7 channels. Effect in mesenteric, but not renal arteries. |
| Lindman et al. 2018 Ipertension [87] |
In vitro rat model | WK RA Vs WK MA |
The role of microtubule stability on β-adrenoceptor signaling in rat renal and mesenteric arteries. | Microtubule disruption improves the β-adrenoceptor-mediated relaxations of mesenteric and renal arteries. |
| Xu et al. 2016 [91] Arterioscler Thromb Vasc |
Mice model | Apolipoprotein E knockout mice LRA Vs Apolipoprotein E knockout mice LCCA |
Role of Kca3.1 I in macrophage polarization. Relationship to plaque instability. | Block of kCa3.1 suppresses plaque instability. |
| Hu et al. 2016 [91] Arterioscler Thromb Vasc |
Mice model | Ad-Bmp4 Ad-Pdgfa-shRNA |
Whether PDGF mediates BMP4-induced endothelial dysfunction in diabetes mellitus. | PDGF-AA impairs endothelium-dependent vasodilation. PDGF-AA mediates BMP4-induced adverse effect on endothelial cell function through SMAD1/5- and SMAD4-dependent mechanisms. Inhibition of PGDF-AA ameliorates vascular dysfunction. |
| Chen 2017 [92] Arterioscler Thromb Vasc |
Mice model | EC-specific P2Y2R-deficient mice EC-specific P2Y2R knockout mice onto an ApoE−/− |
Role of endothelial P2Y2R in the pathogenesis of atherosclerosis. | EC-specific P2Y2R deficiency reduces atherosclerotic burden and promotes plaque stability in ApoE−/− mice. |
Abbreviations: Ad-Bmp4, overexpress Bmp4; Ad-Pdgfa-shRNA, knockdown Pdgfa; AMPK, AMP-activated protein kinase; AMPKα2, EC-specific AMPKα2 knockout mice; ApoE−/−; knockout mice apoliprothein E; BMP4, Bone morphogenic protein 4; CTRP9, C1q/tumor necrosis factor-related protein-9; db/db; streptozotocine-induced diabetic mice; eAMPK(−/−), endothelial-specific AMPK-knockout mice; EC, endothelial cell; eAMPK(flox/flox, littermate control; EDH, endothelium-dependent hyperpolarization; EPAC, exchange protein directly activated by cAMP; HPH, hypoxia-induced pulmonary hypertension; KCa3.1, calcium-activated potassium channel type 3.1; Kv7, potassium channel type 7; LCZ696, receptor-neprilysin inhibitor sacubitril/valsartan; LCCA, left common carotid artery; LRA, left renal artery; MA, mesenteric artery; miR-34a, endothelial microRNA-34a; NO, nitric oxide; P2Y2R, Nucleotide P2Y2 receptor; PAH, pulmonary arterial hypertension; PDGF, platelet-derived growth factors; PMVEC; pulmonary microvascular endothelial cell; PKGIα, protein kinase G I-α; PVAT, perivascular adipose tissue; RA, renal artery; SHRs, spontaneously hypertensive rats; SIRT1, sirtuin 1; SMAD, Superfamily Mothers Against Decapentaplegic; WK, Wistar Kyoto.