Impairment of endothelial Pannexin1-TRPV4 signaling and flow-induced vasodilation in obesity-induced pulmonary hypertension
Authors: Daneva Zdravka , Chen Yen-Lin , Kuppusamy Maniselvan , Sonkusare Swapnil 
Published: May 2023

Obesity is a highly prevalent and debilitating disease that significantly contributes to the development of other pathologies, such as pulmonary hypertension (PH). However, the mechanisms triggering obesity-induced PH (OiPH) are currently unknown. Endothelial cell (EC) Ca2+ signals dilate small pulmonary arteries (PAs) and maintain a low resting pulmonary arterial pressure (PAP). Impairment of endothelial Ca2+ signaling mechanisms is a crucial contributor to elevated PAP in PH. Although PAs are a “high-flow” vascular bed, flow-induced endothelial Ca2+ signaling mechanisms have not been investigated in OiPH. In this regard, we recently showed that Ca2+ influx through endothelial transient receptor potential vanilloid 4 (TRPV4EC) ion channels dilates PAs and lowers resting PAP (Daneva et al., PNAS, 2021). Moreover, flow/shear stress (F/SS) activates the efflux of adenosine triphosphate (ATP) through endothelial Pannexin 1 (Panx1EC) in PAs. Panx1EC-effluxed ATP, in turn, stimulates endothelial purinergic P2Y2 receptor (P2Y2REC) to increase TRPV4EC channel activity (Daneva et al., eLife, 2021). Therefore, I hypothesized that impaired Panx1EC-P2Y2REC-TRPV4EC signaling axis reduces flow-induced dilation of PAs and elevates PAP in OiPH. Right ventricular systolic pressure, an indicator of PAP, was significantly higher in mice exposed to a high-fat diet (HFD, 60%, 24 weeks) compared to normal chow-fed mice, confirming OiPH in these mice. F/SS (4–15 dynes/cm2)-induced dilation was drastically reduced in small PAs (~ 50 μm), cannulated at both ends and pressurized to 15 mm Hg, from HFD mice, possibly indicating impaired flow-induced endothelial signaling in OiPH. Confocal Ca2+ imaging studies in fluo-4-loaded PAs showed that the baseline and agonist (GSK1016790A)-induced activity of TRPV4EC sparklets (unitary Ca2+ influx signals through TRPV4EC channels) is reduced in HFD mice compared to normal mice, confirming a decrease in TRPV4EC channel activity in OiPH. F/SS (4–15 dynes/cm2) resulted in increased activity of TRPV4EC sparklets in PAs from normal mice, but not in PAs from HFD mice, suggesting that flow-induced TRPV4EC activity is reduced in OiPH. Bioluminescence measurements of extracellular ATP concentration showed lower baseline ATP levels in PAs from HFD mice than normal mice. Importantly, F/SS (4 – 15 dynes/cm2) increased ATP efflux in PAs from normal mice, but not in PAs from HFD mice, indicating that flow-Panx1EC signaling is also impaired in OiPH. Together, these data support the idea that flow-induced Panx1EC-TRPV4EC signaling is impaired in OiPH. Targeting the individual elements of this pathway may provide novel therapies in OiPH. Future studies will assess the signaling linkages of the flow-Panx1EC-P2Y2REC-TRPV4EC signaling axis in OiPH.

R01 HL142808, R01 HL146914, R01 HL157407 to Dr. S.K. Sonkusare; APS Postdoctoral Fellowship Award to Dr. Z. Daneva

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.