Role of VEGF-B in the lung during development of chronic hypoxic pulmonary hypertension

Angiogenic factors exert protective effects on the lung. To investigate the effect of VEGF-B, a factor coexpressed in the lung with VEGF-A, we assessed chronic hypoxic pulmonary hypertension in VEGF-B knockout mice ( VEGF-B -/-) and in rats with lung overexpression of VEGF-B induced by adenovirus transfer. No significant difference in pulmonary hemodynamics, right ventricular hypertrophy, distal vessel muscularization, or vascular density was found between VEGF- B-/- and control mice after 3 wk of hypoxia. When overexpressed, VEGF-B-167 or VEGF-B-186 had protective effects similar to those of human VEGF-A(165). Lung endothelial nitric oxide synthase ( eNOS) expression was increased by 5 days of hypoxia or VEGF- A adenovirus vector ( Ad. VEGF- A) overexpression, whereas VEGF-B-167 or VEGF-B-186 had no effect. With hypoxia or normoxia, the wet-to-dry lung weight ratio was increased 5 days after Ad. VEGF- A administration compared with control (Ad.nul), Ad.VEGF- B-167, or Ad.VEGF-B-186. Endogenous VEGF- B does not counteract the development of hypoxic pulmonary hypertension. However, when overexpressed in the lung, VEGF- B can be as potent as VEGF- A in attenuating pulmonary hypertension, although it has no effect on eNOS expression or vascular permeability.