Abstract 18288: Flow Shear Stress and Osmotic Stretch Both Enhance Intracellular Ca2+ in PASMC From Patients With Idiopathic Pulmonary Arterial Hypertension
Idiopathic pulmonary arterial hypertension (IPAH) is a fatal and progressive disease which is attributed to elevated pulmonary arterial pressure and pulmonary vascular resistance due in part to sustained pulmonary vasoconstriction and vascular remodeling. Pulmonary arterial smooth muscle cells (PASMC) are normally shielded from exposure to shear stress and sense small flow shear through transmural interstitial flow driven by transvascular pressure differential. However, in the context of endothelial injury or enhanced vascular permeability caused by increased pulmonary arterial pressure, PASMC are exposed to shear stress or to enhanced transmural interstitial flow. The decreased extracellular osmotic pressure caused by enhanced vascular permeability will exert osmotic stretch on PASMC. Both shear stress and osmotic stretch increase cytosolic Ca2+ concentration ([Ca2+]cyt). An increase in [Ca2+]cyt in PASMC is a major trigger for vasoconstriction and a key stimulus for cell proliferation, which contribute to vascular remodeling. We show here that flow shear stress and osmotic stretch induced increased [Ca2+]cyt in PASMC from patients with IPAH compared with control. Flow shear induced enhanced transient and plateau [Ca2+]cyt and larger Ca2+ oscillation amplitude in IPAH PASMC than in control. Expression of TRPM7, a Ca2+ channel implicated in response to shear stress, is increased in IPAH PASMC. TRPM7 blockers 2-APB and SK&F96365 inhibited flow shear-induced enhanced [Ca2+]cyt in control and IPAH PASMC, and the TRPM7 agonist bradykinin induced enhanced [Ca2+]cyt in IPAH PASMC than in control. Osmotic stretch also induced a transient increase in [Ca2+]cyt in IPAH PASMC, but not in control. La3+, an inhibitor of TPRM3, a Ca2+ channel important for responses to osmotic stress, completely inhibited osmotic stretch-induced increase in [Ca2+]cyt in IPAH PASMC. Furthermore, the TRPM3 agonist PregS induced a transient increase in [Ca2+]cyt in IPAH PASMC but not in control. These results demonstrate that flow shear stress and osmotic stretch induce enhancement of [Ca2+]cyt in IPAH PASMC through the Ca2+ channels, TRPM7 and TRPM3, and that mechanical sensitive channels TRPM7 and TRPM3 play a critical role in PAH by modulating [Ca2+]cyt homeostasis.
- © 2013 by American Heart Association, Inc.