Role of vascular endothelial growth factor receptor 1 and vascular endothelial growth factor receptor 2 in the vasodilator response to vascular endothelial growth factor in the neonatal piglet lung

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Abstract
Objective: Vascular endothelial growth factor (VEGF) regulates vascular proliferation and causes vasodilation. In the pulmonary circulation, the vasorelaxing effect of VEGF has been attributed to nitric oxide, whereas in other vascular beds, prostacyclin and other mechanisms are also involved. This vascular effect follows binding to two receptors, VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2), the latter of which is thought to be the main receptor responsible for the vasorelaxing effect of VEGF. The role of VEGFR1 in the neonatal pulmonary vasculature remains to be determined. Design: Prospective randomized laboratory investigation. Setting: Animal laboratory. Subjects: Newborn Yorkshire-Landrace piglets. Interventions: To determine the mechanisms of action of VEGF in the neonatal pulmonary vasculature, the effect of VEGF (10−12–10−9 M) was tested in isolated perfused piglet lungs, alone and in the presence of a VEGFR2 kinase inhibitor, NG-nitro-l-arginine (L-NNA), indomethacin (Indo), L-NNA + Indo, and GF109203X, a protein kinase C inhibitor. The effect of a VEGFR1 agonist, placenta growth factor (PlGF), was also studied with or without L-NNA. Perfusate was collected, and cyclic guanosine monophosphate (cGMP), as well as 6-keto prostaglandin F1α and thromboxane B2, the stable metabolites of prostacyclin and thromboxane, respectively, was measured. Measurements and Main Results: VEGF caused vasorelaxation with a concomitant increase in cGMP. PlGF also decreased vascular tone and increased cGMP. VEGFR2 kinase inhibitor did not prevent the reduction in perfusion pressure seen with VEGF but blocked the increase in cGMP. Pretreatment with L-NNA completely inhibited VEGF and PlGF vasodilation and prevented the increase in cGMP seen with both agonists. Pretreatment with Indo or GF109203X did not reduce the dilator response to VEGF. Conclusions: VEGF vasodilation may follow nitric oxide release in the piglet pulmonary circulation. VEGF vasorelaxation may not only occur through binding to VEGFR2, since PlGF, the specific VEGFR1 agonist, also causes vasodilation. Therefore, vasodilator response to VEGF may involve both types of receptor in the neonatal piglet pulmonary vasculature.