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Decreased Cyclic GMP-protein Kinase G signaling impairs Angiogenesis in a Lamb Model of Persistent Pulmonary Hypertension of Newborn.

Impaired angiogenesis function of pulmonary artery endothelial cells (PAEC) contributes to persistent pulmonary hypertension of the newborn (PPHN). Decreased nitric oxide (NO) levels in PPHN lead to impaired mitochondrial biogenesis and angiogenesis in the lung; the mechanisms remain unclear. We hypothesized that decreased cGMP-Protein kinase G (PKG) signaling downstream of NO leads to decreased mitochondrial biogenesis and angiogenesis in PPHN. PPHN was induced by ductus arteriosus constriction from 128-136d gestation in fetal lambs. Controls were gestation matched lambs without ductal constriction. PAEC isolated from PPHN lambs were treated with soluble guanylyl cyclase activator, cinaciguat, PKG activator, 8-Br-cGMP or phosphodiesterase-V inhibitor, sildenafil. Lysates were immunoblotted for mitochondrial transcription factors and electron transport chain (ETC) complex proteins I-V. In vitro angiogenesis of PAEC was evaluated by tube formation and scratch recovery assays. cGMP levels were measured by enzyme immunoassay. Fetal lambs with ductal constriction were given sildenafil or control saline by continuous infusion in utero and lung histology, capillary counts, vessel density and right ventricular pressure were assessed at birth. PPHN PAEC showed decreased mitochondrial transcription factors, ETC proteins, and in vitro tube formation and cell migration; these were restored by cinaciguat, 8-Br-cGMP and sildenafil. Cinaciguat and sildenafil increased cGMP levels in PPHN PAEC. Radial alveolar and capillary counts and vessel density were lower and RV pressure and Fulton index higher in PPHN lungs; these were improved by in utero sildenafil infusion. cGMP-PKG signaling is a potential therapeutic target to restore decreased mitochondrial biogenesis and angiogenesis in PPHN.