VEGF Trap Abolishes Shear Stress‐ and Overload‐Dependent Angiogenesis in Skeletal Muscle

Abstract

Objective: To determine which elements of the angiogenic process are controlled by VEGF under physiological conditions. Methods: VEGF Trap was administered at 10 mg · kg⁻¹ by subcutaneous injection twice weekly to mice, which were subject to one of two established angiogenic stimuli: ( 1 ) increasing blood flow by administration of prazosin (50 mg L⁻¹); ( 2 ) muscle overload by extirpation of a synergist. Angiogenesis was determined by calculating capillary to fiber ratio (C:F), and proliferating cell nuclear antigen (PCNA) staining localized to capillaries or the interstitium used to measure cell proliferation. Characteristic ultrastructural changes were quantified using electron microscopy. Results: Administration of VEGF Trap abolished the increases in C:F seen in both models, and prevented growth of luminal filopodia and large vacuole formation. Overload‐induced proliferation associated with capillaries was reduced, along with endothelial cell number abluminal sprouts and basement membrane breakage. However, interstitial proliferation remained high, along with the increased capillary association of pericytes and fibroblasts. Conclusions: VEGF is required for both models of angiogenesis, although some morphological changes lie upstream, or are independent of, VEGF involvement. The abolition of angiogenesis in a model unaffected by NO inhibition shows that NO is not required for all VEGF‐dependent angiogenesis in vivo.