TRPC1 and TRPC6 Regulate Chronic Hypoxia‐induced Vascular Tone, Vasoreactivity and Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) due to chronic hypoxia (CH) exposure is associated with increased vascular tone, altered reactivity to agonists and profound vascular remodeling, which are associated with alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells. We have previously demonstrated that transient receptor potential channel 1 and 6 (TRPC1 and TRPC6) channels were upregulated in CH rats. However, whether TRPC1 and TRPC6 genes contribute to elevated pulmonary pressure and how these cation channels affect vascular tone, reactivity and remodeling remain unclear. Here we found that CH caused a significant increase in the vascular tone of intrapulmonary arteries (IPAs) of wild‐type (WT) mice, but the enhancement was attenuated in TRPC1 null (trpc1−/−) mice and TRPC6 null (trpc6−/−) mice. Moreover, the enhanced vascular reactivity to serotonin observed in endothelium denuded IPAs of hypoxic mice was obliterated in trpc6−/− mice. Morphological analysis indicated that the muscularization in small PAs (<100 μm) of CH mice was significantly less in trpc1−/− and trpc6−/− mice compared to WT. In extension of these results, the elevated pulmonary arterial pressure and right heart hypertrophy were significantly suppressed in trpc1−/− mice. Our results hence provide strong evidence supporting the pathophysiological roles of TRPC1 and TRPC6 gene in the development of PH. (Supported by NIH)