Endothelial TRPV4 Channel Regulation of Pulmonary Arterial Pressure

Pulmonary hypertension is a degenerative disorder affecting the pulmonary circulation and is characterized by increases in pulmonary vascular resistance and pulmonary arterial pressure. Loss of endothelium-dependent vasodilation in resistance vessels contributes to the pathogenesis of pulmonary hypertension. However, the physiological and pathological mechanisms that regulate endothelial function in health and disease remain poorly understood. Spatially localized increases in intracellular endothelial Ca2+ in resistance pulmonary arteries regulate vasodilation and overall pulmonary arterial pressure. Endothelial transient receptor potential vanilloid 4 (TRPV4-EC) channels are a major source of Ca2+ influx in resistance pulmonary arteries but the role of TRPV4-EC channel activity on endothelial function has remained unexplored. Work in this thesis investigates the hypothesis that TRPV4-EC channel activity promotes vasodilation in resistance pulmonary arteries thereby maintaining a low resting pulmonary arterial pressure.

Our results demonstrate that TRPV4-EC channel activity promotes vasodilation in resistance pulmonary arteries through the activation of endothelial nitric oxide synthase and subsequent release of nitric oxide (NO). Furthermore, caveolin-1 (Cav-1) was identified as a novel regulator of TRPV4-EC channels which potentiates TRPV4-EC channel activity. Loss of Cav-1-dependent activation of TRPV4-EC channels leads to endothelial dysfunction and an increase in pulmonary arterial pressure, revealing TRPV4-EC channels as important regulators of normal resting pulmonary arterial pressure. In pulmonary hypertension, endothelial Cav-1-TRPV4-EC channel signaling is impaired resulting in the loss of vasodilation, thus increasing pulmonary arterial pressure. Elevated production of the reactive nitrogen species, peroxynitrite, is responsible for the impairment of Cav-1-dependent regulation of TRPV4-EC channel activity in pulmonary hypertension. Future studies should investigate the mechanisms by which peroxynitrite modifies Cav-1-dependent potentiation of TRPV4-EC channel activity in hopes of developing novel therapeutic targets for the treatment of pulmonary hypertension.