TRPC4-mediated calcium signals accelerate vascular remodeling in pulmonary arterial hypertension

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Abstract Pulmonary arterial hypertension (PAH) is an incurable disease of elevated pulmonary artery pressure that culminates in death due to right heart failure. The etiology of PAH is comprised of increased vasoconstriction in resistance arteries and remodeling of the arterial microcirculation. All current therapies for PAH target vasoconstriction, but patient survival has not improved because remodeling remains irreversible. Thus, there has been considerable impetus to determine the mediators of remodeling in PAH. Members of the transient receptor potential (TRP) family ion channels have been implicated as drivers of vascular proliferation and remodeling in PAH. Our lab has shown that TRPC4, a subtype of the canonical TRP family, increases mortality and vascular lesion number and severity in PAH. A separate mechanism of hemodynamic perturbations resulting in turbulent or oscillatory endothelial shear stress has also been associated with increased vascular resistance and remodeling in PAH. Given that both TRPC4 and shear-induced signals are linked by the nexus of intracellular calcium, we hypothesize that TRPC4 and shear-mediated endothelial calcium signals will exacerbate lesion formation in PAH. Therefore, the goal of this proposal is to determine the interaction between TRPC4-dependent endothelial calcium signals and oscillatory shear stress as a driver of occlusive remodeling in PAH. Determining the underlying basis of vascular remodeling in PAH may lead to a novel class of PAH therapeutics for extending patient survival and improving quality of life. As a candidate trained in the quantitative areas of computational modeling and animal physiology at the Center for Lung Biology, I am well suited to investigate the determinants of vascular remodeling in PAH. Furthermore, the goals of this award are aligned with my specific career goals of gaining research expertise, education, and professional skills on my path to career independence. The proposed research plan takes advantage of the robust institutional environment and considerable expertise in the pathophysiology of PAH. The project mentor, Dr. Troy Stevens, and additional personnel are well known experts in the fields of endothelial biology, vascular physiology, and pulmonary hypertension. Additionally, our state-of-the-art laboratories have the requisite equipment to complete this work.