Impaired Endothelial Caveolin‐1‐TRPV4 Channel Signaling Contributes to Endothelial Dysfunction in Pulmonary Hypertension

Impaired endothelium‐dependent vasodilation is a key contributor to elevated pulmonary arterial pressure (PAP) in pulmonary hypertension (PH). While the mechanisms of pathogenesis of PH remain elusive, recent studies show that spatially localized Ca 2+ influx via endothelial transient receptor potential vanilloid 4 (TRPV4 EC ) channels promotes vasodilation in resistance‐sized pulmonary arteries (PAs) by activating endothelial nitric oxide synthase (eNOS) and releasing nitric oxide (NO). Caveolin‐1 (Cav‐1 EC ) is an essential structural protein within the pulmonary endothelium, where it has been found to associate with TRPV4 EC channels in cultured endothelial cells. We hypothesized that Cav‐1 EC regulates TRPV4 EC channel activity and PAP, and that impaired Cav‐1 EC ‐TRPV4 EC signaling contributes to elevated PAP in PH. To test these hypotheses, we used right ventricular systolic pressure (RVSP) and PAP measurements in normoxic or chronic hypoxic Cav‐1 EC −/− and TRPV4 EC −/− mice, and pressure myography and high‐speed Ca 2+ imaging studies in PAs from these mice. TRPV4 EC channel activity and TRPV4 EC ‐mediated vasodilation were significantly impaired in PAs from Cav‐1 EC −/− mice, suggesting that Cav‐1 EC enhances TRPV4 EC channel activity in PAs. Purinergic signaling plays an important role in pulmonary circulation, and we recently identified adenosine triphosphate (ATP) as a novel physiological activator of TRPV4 EC channels in PAs. ATP activation of TRPV4 EC channels was abolished by protein kinase C (PKC) inhibition, and was absent in the arteries from Cav‐1 EC −/− mice, supporting a Cav‐1 EC ‐PKC‐TRPV4 EC signaling that enables ATP activation of TRPV4‐ EC channels. Resting RVSP and PAP were elevated in Cav‐1 EC −/− and TRPV4 EC −/− mice supporting the concept that Cav‐1 EC ‐TRPV4 EC signaling lowers resting PAP. Moreover, exposure to chronic hypoxia (CH, 3 weeks) resulted in higher increases in RVSPs in Cav‐1 EC −/− and TRPV4 EC −/− mice when compared to the respective wild‐type control mice, suggesting that Cav‐1 EC ‐TRPV4 EC channel signaling is protective against CH‐induced PH. We further used two well‐established models of PH— CH and sugen 5416 injection + CH. TRPV4 EC channel activity, and ATP‐ and PKC‐activation of TRPV4 EC channels were impaired in PAs from both the models of PH, suggesting that Cav‐1 EC ‐PKC‐TRPV4 EC signaling may be impaired in PH. Taken together, these results suggest that Cav‐1 EC ‐PKC‐TRPV4 EC signaling lowers resting PAP, and is impaired in PH. Deciphering the mechanisms that impair the Cav‐1 EC ‐PKC‐TRPV4 EC signaling in PH may lead to novel therapeutic strategies to restore endothelium‐dependent vasodilation in PH. Support or Funding Information HL121484‐01, HL‐138496