Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus.
Platelet-derived growth factor (PDGF) is a potent smooth muscle cell mitogen that may contribute to smooth muscle hyperplasia during the development of chronic pulmonary hypertension (PH). We studied changes in PDGFalpha- and beta-receptor and ligand expression in lambs with chronic intrauterine PH induced by partial ligation of the ductus arteriosus (DA) at gestational age 124-128 days (term = 147 days). Western blot analysis performed on whole lung homogenates from PH animals after 8 days of DA ligation showed a twofold increase in PDGFalpha- and beta-receptor proteins compared with age-matched controls (P < 0.05). Lung PDGF-A and -B mRNA expression did not differ between PH and control animals. We treated PH animals with NX1975, an aptamer that selectively inhibits PDGF-B, by infusion into the left pulmonary artery for 7 days after DA ligation. NX1975 reduced the development of muscular thickening of small pulmonary arteries by 47% (P < 0.05) and right ventricular hypertrophy (RVH) by 66% (P < 0.02). Lung PDGFalpha- and beta-receptor expression is increased in perinatal PH, and NX1975 reduces the increase in wall thickness of small pulmonary arteries and RVH in this model. We speculate that PDGF signaling contributes to structural vascular remodeling in perinatal PH and that selective PDGF inhibition may provide a novel therapeutic strategy for the treatment of chronic PH.
Balasubramaniam
Vivek
V
Pediatric Heart Lung Center and Section of Pediatric Pulmonary Medicine, University of Colorado School of Medicine and The Children's Hospital, Denver, Colorado 80218, USA. vivek.balasubramaniam@uchsc.edu
Le Cras
Timothy D
TD
Ivy
D Dunbar
DD
Grover
Theresa R
TR
Kinsella
John P
JP
Abman
Steven H
SH
D000818:Animals; D002908:Chronic Disease; D005260:Female; D005315:Fetal Diseases / Q000473:pathology / Q000503:physiopathology; D015870:Gene Expression / Q000502:physiology; D005865:Gestational Age; D006976:Hypertension, Pulmonary / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008024:Ligands; D009131:Muscle, Smooth, Vascular / Q000473:pathology* / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D011247:Pregnancy; D011652:Pulmonary Circulation / Q000502:physiology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D012756:Sheep; D015398:Signal Transduction / Q000502:physiology
D008024:Ligands; D010982:Platelet-Derived Growth Factor; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta