Increased Vascular Endothelial Growth Factor Production in the Lungs of Rats with Hypoxia-induced Pulmonary Hypertension

Abstract

Vascular endothelial growth factor (VEGF) is a potent mitogenic and permeability factor targeting predominantly endothelial cells. At least two tyrosine kinase receptors, Flk-1 and Flt-1, mediate its action and are mostly expressed by endothelial cells. VEGF and VEGF receptor expression are upregulated by hypoxia in vivo and the role of VEGF in hypoxia-induced angiogenesis has been extensively studied in a variety of disease entities. Although VEGF and its receptors are abundantly expressed in the lung, their role in hypoxic pulmonary hypertension and the accompanying vascular remodeling are incompletely understood. We report in this in vivo study that hypoxia increases mRNA levels for both VEGF and Flk-1 in the rat lung. The kinetics of the hypoxic response differ between receptor and ligand: Flk-1 mRNA showed a biphasic response to hypoxia with a significant, but transient, rise in mRNA levels observed after 9-15 h of hypoxic exposure and the highest levels noted after 3 wk. In contrast, VEGF mRNA levels did not show a significant increase with acute hypoxia, but increased progressively after 1-3 wk of hypoxia. By in situ hybridization, VEGF mRNA was localized predominantly in alveolar epithelial cells with increased signal in the lungs of hypoxic animals compared with controls. Immunohistochemical staining with anti-VEGF antibodies localized VEGF peptide throughout the lung parenchyma and was increased in hypoxic compared with normoxic animals. Furthermore, hypoxic animals had significantly higher circulating VEGF concentrations compared with normoxic controls. Lung vascular permeability as measured by extravasation of Evans Blue dye was not significantly different between normoxic and hypoxic animals, although a tendency for increased permeability was seen in the hypoxic animals. These findings suggest a possible role for VEGF in the pulmonary response to hypoxia.

Changes in Expression of Vascular Endothelial Growth Factor and Its Receptors in Neonatal Hypoxia-Induced Pulmonary Hypertension

“…For example, MataGreenwood et al (21) noted that whole-lung VEGF expression was increased in a fetal lamb model of pulmonary hypertension with increased pulmonary blood flow. In addition, lung VEGF expression was found to be increased in the adult rat with hypoxia-induced pulmonary hypertension (27,28). Furthermore, VEGF was augmented in lungs of newborn infants with congenital diaphragmatic hernia and pulmonary hypertension (29).…”

Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

“…Six-to 8-week-old HO-1 transgenic mice and their nontransgenic littermates or age-matched nontransgenic mice were exposed to normobaric hypoxia (8-10% oxygen) or normoxia for the indicated time as described previously (14). Animals were killed by lethal injection of sodium pentobarbital.…”

Endothelial Dysfunction in Pulmonary Hypertension

“…A change in the endothelial cell permeability may result from direct injury; from the exuberant production of VEGF by alveolar epithelium in response to hypoxia 74 ; or from actions of inflammatory mediators, cytokines, and oxidants. 75 Mechanical stress as well as mediators such as thrombin can mediate morphological changes in endothelial cells and widening of the intercellular junctions.…”