Adventitial angiogenesis and osteopontin expression induced by local VEGF reduces aortic calcification in a model of coarctation repair

Objectives: Vascular calcification is a common pathologic and precisely regulated process involving bone-associated proteins such as osteopontin (OPN). In a model of coarctation repair, we investigated mechanisms by which recombinant human vascular endothelial growth factor ₁₆₅ (rhVEGF₁₆₅) protects the arterial wall from severe vascular remodeling including calcification, a newly discovered biologic action of VEGF.

Material and Methods: In a rabbit model of thoracic aortic end-to-end anastomosis that simulates cardiovascular intervention, rhVEGF₁₆₅ at a dose of 0.75µg (VEGF, n=19) or albumin (control, n=19) was delivered intraluminally and on the serosal surface. Animals were sacrificed and aortic tissue was evaluated by western blotting, immunohistochemistry, and immunofluorescence at 4, 8, 24 hours, 1 week, and 1 month, postoperatively.

Results: All controls revealed extensive aortic medial calcification at 1 month, whereas calcification was significantly reduced or absent with VEGF treatment. Compared to controls, VEGF treatment resulted in an earlier infiltration of macrophages in the vessel media (at 8 hours: 5.7±2.3 macrophages/hpf in control vs. 32.1±7.5 in VEGF-treated aortas; p<0.001), whereas controls showed an increase in macrophages starting at 1 week (24.1±6.9 vs. 4.3±1.8; p<0.001). OPN expression was transiently elevated and detected in macrophages and endothelial cells in VEGF-treated vessels and adventitial microvascular density was significantly increased by one week (9.5±0.43 vs. 25.0±1.3; p<0.001).

Conclusions: In a model of coarctation repair, exogenous VEGF is capable of increasing adventitial angiogenesis and shifting macrophage infiltration and OPN expression within the media to an earlier time point thereby promoting prompt repair and diminishing vascular remodeling and calcification after acute vascular injury.