R35HL171538

Ion channels and membrane receptors in pulmonary arterial hypertension - project summary/abstract

Pulmonary arterial hypertension (PAH) is a fatal and progressive disease with unknown etiology and poor survival rate. Pulmonary vasoconstriction, vascular remodeling and occlusive intimal lesion are the major causes for the elevated pulmonary vascular resistance (PVR) in PAH.

A rise in cytosolic Ca2+ concentration ([Ca2+]CYT) is a trigger for pulmonary arterial smooth muscle cell (PASMC) contraction (and vasoconstriction) and a stimulus for PASMC proliferation/migration (and vascular remodeling). In addition, the contractile-to-proliferative phenotypic transition (CPPT) in PASMC and endothelial-to-mesenchymal transition (ENDMT) in pulmonary arterial endothelial cells (PAEC) are implicated in the development of pulmonary vascular remodeling and obliterative intimal lesion in PAH.

We recently found that PIEZO1, a mechanosensitive cation channel, and CALHM1 (calcium homeostasis modulator 1), a voltage-gated cation and ATP channel, are upregulated during CPPT and involved in vascular remodeling in PAH/PH. Upregulated PIEZO1 in PAEC enhances ENDMT via the Ca2+/AKT/MTOR-JAGGED1 (JAG-1) signaling axis and is involved in the development of occlusive vascular lesion and concentric vascular remodeling in animals with experimental pulmonary hypertension (PH).

In addition, we identified GPR91 (a succinate-activated GPCR) and GPR68 (a mechanosensitive GPCR) that are involved in the development of pulmonary vascular remodeling in PAH/PH. The central hypothesis is that ionic (channel) remodeling is required for phenotypic transition of PASMC/PAEC. Upregulated channels (PIEZO1/CALHM1) and receptors (GPR68/91) are required for causing pathogenic overgrowth of PASMC/EC through activation of Ca2+- sensitive signaling and compartmentation of AKT/MTORC1 signaling, and contribute to vascular remodeling and occlusive intimal lesion in PAH.

The overall goals of this study are to examine: 1) gene expression profile associated with the phenotypic transition of PASMC (CPPT) and PAEC (ENDMT), 2) cellular and molecular mechanisms involved in CPPT in human PASMC, 3) whether PIEZO1 and mechanosensitive Ca2+ signaling contribute to inducing and regulating ENDMT in PAEC and whether endothelial PIEZO1 is involved in the development of PH, 4) how compartmentalized AKT/MTORC1 signaling and spatiotemporal Ca2+ signaling are involved in ENDMT in PAEC and enhanced PAEC proliferation in PAH/PH, 5) whether viroporins (e.g., SARS- COV-2 E protein) form non-selective cation channels to promote Ca2+ influx and stimulate PASMC/EC proliferation, and 6) whether and how Ca2+ influx through upregulated cation channels and activation of selected receptors contribute to regulation of inflammasome in PASMC/EC.

The importance of this research program is in its integrative design and translational potential in which we will define the pathogenic mechanism, identify new therapeutic targets, and develop novel therapies for PAH/PH based on our studies on mechanosensitive channels/receptors and Ca2+ signaling in PASMC and PAEC.

University Of Florida

NOT APPLICABLE

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Jupiter, Florida 33458 United States

Single Zip Code

NHLBI Outstanding Investigator Award (OIA) (R35 Clinical Trial Optional) (RFA-HL-23-004)

Amendment Since initial award the total obligations have increased 242% from $1,106,000 to $3,783,752.