Regulated Angiogenesis and Vascular Regression in Mice Overexpressing Vascular Endothelial Growth Factor in Airways

Abstract

Angiogenesis and vascular remodeling occurs in many inflammatory diseases, including asthma. In this study, we determined the time course and reversibility of the angiogenesis and vascular remodeling produced by vascular endothelial growth factor (VEGF) in a tet-on inducible transgenic system driven by the CC10 promoter in airway epithelium. One day after switching on VEGF expression, endothelial sprouts arose from venules, grew toward the epithelium, and were abundant by 3 to 5 days. Vessel density reached twice baseline by 7 days. Many new vessels were significantly larger than normal, were fenestrated, and penetrated the epithelium. Despite their mature appearance at 7 days suggested by their pericyte coat and basement membrane, the new vessels started to regress within 3 days when VEGF was switched off, showing stasis and luminal occlusion, influx of inflammatory cells, and retraction and apoptosis of endothelial cells and pericytes. Vessel density returned to normal within 28 days after VEGF withdrawal. Our study showed the dynamic nature of airway angiogenesis and regression. Blood vessels can respond to VEGF by sprouting angiogenesis within a few days, but regress more slowly after VEGF withdrawal, and leave a historical record of their previous extent in the form of empty basement membrane sleeves.