Abstract
[Figure: see text].
Highlights
GPR35 (G-protein–coupled receptor 35) is a poorly characterized receptor that has garnered increased interest as a therapeutic target through its implications in a range of inflammatory and cardiovascular diseases, but its biological functions stay largely unknown
This study uncovered novel molecular mechanisms underlying the benefit of GPR35 inhibition on endothelial function and provide proof-of-concept evidence for GPR35-targeted therapeutic strategies in regulating blood pressure, paving the avenue for future drug discoveries based on this GPR in cardiovascular and metabolic disorders
The functional assays suggested that knocking down GPR35 in HAECs significantly improved migration (Figure 2A, n=6 per group, Mann-Whitney U test P=0.004) and 3D tube formation (Figure 2B, n=6 per group, Mann-Whitney U test P=0.002)
Summary
GPR35 (G-protein–coupled receptor 35) is a poorly characterized receptor that has garnered increased interest as a therapeutic target through its implications in a range of inflammatory and cardiovascular diseases, but its biological functions stay largely unknown. Endothelium-derived nitric oxide (NO) is a potent vasodilator that maintains cardiovascular homeostasis.[5] Patients with hypertension or animals possess blunted endothelium-dependent NO-mediated vasodilation,[4,6] which is a valuable indicator for endothelial dysfunction at the early onset of hypertension.[7] The activation of the eNOS (endothelial NO synthase) and the capacity of eNOS to generate NO are tightly controlled by multiple integrative signaling pathways.[8] The deficiency of tetrahydrobiopterin (BH4), the cofactor of eNOS, results in eNOS uncoupling, which switches eNOS to generate superoxide rather than NO, leading. Our data indicate that genetic deletion of GPR35 augments endothelial cell functions in vitro and vasodilation in male animals in vivo This contributes to maintaining normal blood pressure in an experimental hypertensive animal model. These male-biased finding in GPR35’s action on hemodynamic regulation is intriguing, but future studies are needed to investigate underlying mechanisms
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