Peroxisome proliferator-activated receptor- (PPAR) and Rho-kinase (ROCK) regulate smooth muscle cell (SMC) proliferation and contribute to vascular remodeling in adult pulmonary hypertension. Whether these pathways interact to contribute to the development of vascular remodeling in persistent pulmonary hypertension of the newborn (PPHN) remains unknown. We hypothesized that ROCK-PPAR interactions increase SMC proliferation resulting in vascular remodeling in experimental PPHN. Pulmonary artery SMCs (PASMCs) were harvested from fetal sheep after partial ligation of the ductus arteriosus in utero (PPHN) and controls. Cell counts were performed daily for 5 days with or without PPAR agonists and ROCK inhibition. PPAR and ROCK protein expression\/activity were measured by Western blot in normal and PPHN PASMCs. We assessed PPAR-ROCK interactions by studying the effect of ROCK activation on PPAR activity and PPAR inhibition (siRNA) on ROCK activity and PASMC proliferation. At baseline, PPHN PASMC cell number was increased by 38% above controls on day 5. ROCK protein expression\/activity were increased by 25 and 34% and PPAR protein\/activity decreased by 40 and 50% in PPHN PASMC. ROCK inhibition and PPAR activation restored PPHN PASMC growth to normal values. ROCK inhibition increased PPAR activity by 50% in PPHN PASMC, restoring PPAR activity to normal. In normal PASMCs, ROCK activation decreased PPAR activity and PPAR inhibition increased ROCK activity and cell proliferation, resulting in a PPHN hyperproliferative PASMC phenotype. PPAR-ROCK interactions regulate SMC proliferation and contribute to increased PPHN PASMC proliferation and vascular remodeling in PPHN. Restoring normal PPAR-ROCK signaling may prevent vascular remodeling and improve outcomes in PPHN. <\/p>\n
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View post: Peroxisome proliferator-activated receptor- (PPAR) and Rho-kinase (ROCK) regulate smooth muscle cell (SMC) proliferation and contribute to vascular remodeling in adult pulmonary hypertension. Whether these pathways interact to contribute to the development of vascular remodeling in persistent pulmonary hypertension of the newborn (PPHN) remains unknown. Continue reading
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