Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by elevated lung pressures, right heart failure, and premature death. Current therapies fail to prevent disease progression due to their inability to suppress and/or reverse pulmonary arterial smooth muscle cells (PASMCs) driven muscularization of distal microvessels. The origin of these highly proliferative PASMCs remains incompletely understood, but may be closely related to the maladaptive behavior of contiguous pericyte (PC) populations. In addition to providing mural support to capillaries, PCs can differentiate into other cell types in response to stress. We recently reported that human PAH lung PCs share lineage markers and functional properties with PASMCs, such as morphology and contractility. We thus hypothesize that PASMCs in PAH vascular lesions originate from capillary PCs. Fate-mapping of PCs in chronic hypoxia mice revealed that PCs dissociate from capillaries and relocate to precapillary arterioles, where they co-express markers of mature SMCs and contribute to muscularization. Through single cell and bulk RNA-seq analysis, we discovered that the HIF2A/SDF1 signaling pathway is a master regulator of differentiation of PCs into SMC and a major modifier of PC dysfunction in PAH. We propose to: 1) demonstrate that HIF2a/SDF1 activation causes PC dissociation from pulmonary capillaries, 2) define the molecular mechanism by which HIF2a/SDF1 signaling drives PC differentiation into PASMC-like in human and mice, and 3) determine whether manipulation of HIF2a/SDF1 in PCs can alter the severity of vascular remodeling in animal models of PH. This project will provide novel insight into pericyte pathobiology and establish HIF2a/SDF1 as a potential therapeutic target in PAH, for which the first drugs to reverse muscularization and improve outcomes in PAH may be found.

Public Health Relevance

Muscularization of distal microvessels is a major pathological feature of pulmonary arterial hypertension (PAH), but sources of smooth muscle cells (SMCs) found within lesions remain unclear. We show for the first time that lung pericytes act as progenitors for SMCs in both PAH and experimental chronic hypoxia. Through a combination of established cellular assays, novel transgenic mouse models and cutting edge CRISPR gene editing, we will demonstrate that activation of a novel HIF2a/SDF1 signaling pathway is essential for differentiation of pericytes into SMCs and that its manipulation has the potential to facilitate the discovery of novel therapeutic approaches capable of reversing muscularization and restoring pulmonary vascular homeostasis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Fessel, Joshua P
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Boston Children's Hospital
United States
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