Pressure Regulation of Vascular CaV1.2 Channels

. Intravascular pressure is a key stimulus controlling arterial tone and blood flow delivery. Pressure-induced constriction (i.e. myogenic response) is recognized as foundational to vascular hemodynamic control in health and disease. A unique feature of this response is its near complete dependence on vascular smooth muscle (VSM) L-type CaV1.2 channels. While the current dogma assumes that membrane depolarization is the sole factor driving CaV1.2 activation in the myogenic response, pressure itself, independent of electrical coupling, may also directly influence VSM CaV1.2 function. Yet, whether pressure modulates CaV1.2, the underlying mechanisms, and potential (patho)physiological impact are key knowledge gaps that this application aims to address. By utilizing a sophisticated toolkit, exciting and rigorous preliminary data support the central hypothesis that pressure dynamically regulates CaV1.2 spatiotemporal properties via the engagement of PKCα and pS1928 to control VSM contractility and vascular reactivity in health and disease. This hypothesis will be tested in three specific aims. Aim 1 is to test the hypothesis that pressure regulates CaV1.2 spatiotemporal properties in VSM. Aim 2 is to test the hypothesis that pressure regulation of CaV1.2 requires kinase activity and pS1928. Finally, Aim 3 is to test the hypothesis that pressure regulation of CaV1.2 spatiotemporal properties is altered in disease states. The proposal has high translational impact as it will advance understanding of VSM Ca2+ dynamics and its role in setting the myogenic response and nutritive blood flow in health and disease, and it may open new avenues for therapeutic manipulation of CaV1.2 in disease states. Project Number: 1R01HL180444-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Manuel Navedo | Institution: UNIVERSITY OF CALIFORNIA AT DAVIS, DAVIS, CA | Award Amount: $733,371 | Activity Code: R01 | Study Section: Integrative Vascular Physiology and Pathology Study Section[IVPP] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18044401