Pulmonary blood vessel remodeling, both in human and animal pulmonary hypertension, involves several alterations of the pulmonary artery endothelial cell phenotype. The lung contains abundant Vascular Endothelial Growth Factor (VEGF), which is a key regulatory molecule involved in the growt and differentiation of endothelial cells. The PI hypothesizes that VEGF regulates key phenotypic properties of pulmonary endothelial cells, in particular those involved in the interaction between the pulmonary endothelium and the vascular medial smooth muscle cell. VEGF triggers a vasodilator and an anti-smooth muscle proliferative response in the lung to conditions which limi pulmonary blood flow, and the VEGF effect relies on the differential expressio of KDR and Flt VEGF receptors on pulmonary endothelial cells. The PI proposes to test whether VEGF reduces pulmonary vessel remodeling in vivo in rats exposed to chronic hypoxia or to monocrotaline by means of administering recombinant VEGF, or neutralizing VEGF with antibodies or with the VEGF-receptor KDR antagonist SU 65641. The PI proposes that the beneficial effect of VEGF on the hypertensive pulmonary circulation lies in the productio of nitric oxide and prostacyclin by VEGF-stimulated endothelial cells. This hypothesis will be addressed in isolated perfused rat lungs and cultured pulmonary endothelial cells. Inhibition of pulmonary smooth muscle cell growth by nitric oxide or prostacyclin induced by VEGF will be assessed in a co-culture system with pulmonary endothelial cells. To test whether the VEGF receptors KDR and Flt have differential abilities to signal the induction of endothelial cell nitric oxide and prostacyclin by VEGF, the PI will determine nitric oxide and prostacyclin production by porcine aorta endothelial cells permanently transfected with either the KDR or the Flt receptors stimulated with VEGF, and whether Flt expression in DKR-transfected cells modifies VEGF-induced NO and prostacyclin production by the endothelial cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060195-03
Application #
6184134
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1998-04-10
Project End
2001-01-31
Budget Start
2000-04-01
Budget End
2001-01-31
Support Year
3
Fiscal Year
2000
Total Cost
$255,637
Indirect Cost
Name
University of Colorado Denver
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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