Vascular endothelial growth factor induces extracellular matrix proteins and osteopontin in the umbilical artery

Vascular endothelial growth factor (VEGF) is a mitogenic, angiogenic, and potent mediator of vascular permeability. It plays a role in injuries, contributes to edema during the acute stage of tissue damage, and promotes repair during recovery. We recently showed that VEGF serum levels of burn patients with a considerable number of damaged vessels were significantly increased. Here, we study the effects of VEGF on healthy vessels treated with a comparable VEGF concentration achieved in patients suffering heavy burns. VEGF 165 (0.2 mL of 10 ng/mL) or vehicle (saline 0.9%) was intraluminally applied to umbilical arteries for 90 min at 37 degrees C. Then, the cord was perfused for 4 hr. During perfusion, functional and biochemical parameters were kept within normal physiological ranges. Afterward, the vessels were analyzed applying morphometry, sirius red staining, polarization microscopy, Western blot analysis, and immunohistochemistry. Moreover, cultured human umbilical vein endothelial cells (HUVECs) were treated with VEGF or vehicle for 90 min and 5.5 hr to examine extracellular matrix (ECM) proteins and receptor tyrosine kinases. VEGF-treated umbilical arteries showed significant tissue edema and simultaneously an enhancement of laminin and collagen types I, III, and IV compared with control arteries. We detected an increase in Flt-1, Flk-1, osteopontin, and ss(1)-integrin. VEGF induced laminin early in HUVECs as measured by flow cytometry. In parallel, VEGF induced a higher amount of osteopontin, ss(1)-integrin, and both receptor tyrosine kinases in endothelial cells within 90 min. Intraluminal application of VEGF enhances ECM protein, osteopontin, and ss(1)-integrin production of the endothelium, while it still generates tissue edema. VEGF initiates vascular remodeling as early as it generates edema, even if the target vessel is not damaged. Osteopontin and ss(1)-integrin, both induced by VEGF, may play an important role in the vascular remodeling process.