Vascular endothelial growth factor causes pulmonary vasodilation through activation of the phosphatidylinositol-3-kinase-nitric oxide pathway in the late-gestation ovine fetus.
Vascular endothelial growth factor (VEGF) causes vasodilation in adult models of peripheral vascular disease and myocardial ischemia through the acute release of nitric oxide (NO). However, the hemodynamic effects of VEGF and its effects on NO production have not been studied in the developing lung circulation. We hypothesized that VEGF causes fetal pulmonary vasodilation, and that its actions are mediated through the release of endogenous NO. We performed surgery in 16 fetal lambs (125-135 d gestation; term = 147 d), and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery (LPA) to measure blood flow, and a catheter was placed in the LPA for local drug infusion. Pulmonary vascular resistance in the left lung was calculated as pulmonary artery pressure minus left atrial pressure divided by LPA flow. Fetal lambs were treated with brief infusions of recombinant human VEGF (dose, 0.5-2.0 micro g) into the LPA. Recombinant human VEGF infusions acutely increased LPA flow by up to 3-fold (p < 0.02) and decreased pulmonary vascular resistance by 65% (p < 0.05) in a dose-related fashion, without affecting aortic pressure or heart rate. To determine the mechanism of VEGF-induced vasodilation, we studied the effects of nitro-L-arginine, an NO synthase inhibitor, and LY294002, a phosphatidylinositol-3-kinase inhibitor, on the response to VEGF. We found that pretreatment with either nitro-L-arginine or LY294002 completely inhibited the vasodilator response to recombinant human VEGF (p < 0.005). These findings suggest that recombinant human VEGF causes fetal pulmonary vasodilation, and that this response is likely mediated by the release of NO through activation of phosphatidylinositol-3-kinase.
Grover
Theresa R
TR
Pediatric Heart Lung Center and Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado 80045, USA. grover.theresa@tchden.org
Zenge
Jeanne P
JP
Parker
Thomas A
TA
Abman
Steven H
SH
D000818:Animals; D002867:Chromones / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000008:administration & dosage / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D008222:Lymphokines / Q000008:administration & dosage / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011247:Pregnancy; D011652:Pulmonary Circulation / Q000187:drug effects*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012756:Sheep; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014664:Vasodilation / Q000187:drug effects*
D002867:Chromones; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009025:Morpholines; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496314:NOS3 protein, human