Decreased PGC‐1α‐SIRT1 Signaling Leads to Impaired Angiogenesis in Persistent Pulmonary Hypertension of the Newborn (PPHN)

Abstract

IntroductionPPHN is characterized by increased pulmonary vascular resistance (PVR) at birth resulting in hypoxemia. Impaired angiogenesis contributes to high PVR in PPHN. Pulmonary artery endothelial cells (PAEC) in PPHN show decreased mitochondrial respiration, increased apoptosis and impaired angiogenesis. Objective: Investigate the hypothesis that down‐regulation of Peroxisome Proliferator‐Activated Receptor Gamma Co‐Activator‐1α (PGC‐1α) and histone deacetylase, Sirtuin‐1 (SIRT‐1) lead to impaired mitochondrial biogenesis and angiogenesis in PPHN. Methods: PAEC were isolated from fetal lambs with PPHN induced by prenatal ductus arteriosus constriction from 80% to term gestation and matched controls. PGC‐1α and SIRT‐1 levels were evaluated by immunoblotting. PGC‐1α was knocked down in control PAEC and overexpressed in PPHN PAEC to investigate effects on mitochondrial complex proteins I‐V and angiogenesis. Angiogenesis was assessed in vitro by tube formation, cell migration and proliferation. Results: PPHN PAEC had significant decreases in PGC‐1α and SIRT‐1 levels vs. controls (p<0.01). PGC‐1α knockdown in control PAEC lead to decreased tube formation (p<0.0001), cell migration (p<0.01) and proliferation (p<0.0001). PGC‐1α over‐expression in PPHN PAEC lead to significant increases in mitochondrial ETC proteins‐ complex I (p<0.0001), II (p=0.0433), III (p=0.0384), and V (p=0.0462), as well as increased tube formation (p<0.0001), cell migration (p<0.01) and proliferation (p<0.0001).ConclusionCoordinated downregulation of PGC‐1α and SIRT1 contribute to decreased mitochondrial biogenesis and angiogenesis in PPHN. This mechanism offers a new therapeutic target in PPHN.