Young research worker's prize finalists.

[A] ARTERIOGENESIS CAN PROCEED INDEPENDENTLY OF INCREASED BLOOD FLOW: THE EFFECT OF VASCULAR ENDOTHELIAL GROWTH FACTOR ON VASCULAR DEVELOPMENT

T.J.A. Chico, J.M. Greve, H.G. Steinmetz, N. van Bruggen, S. Bunting.

Postnatal vascular development proceeds by angiagenesis (capillary growth) and arteriogenesis (development of larger "collateral" vessels). Angiogenesis is predominantly driven by growth factors, while arteriogenesis is held to be a result of increased shear stress and blood flow. Studying arteriogenesis is hampered by a lack of techniques that can image developing vessels. We developed high resolution magnetic resonance angiography (MRA) capable of visualsing arteriogenesis and used it to study the role of nitric oxide in the vascular response to VEGF.

Methods: 88 male C57 b16 mice treated chronically with or without oral L-NAME (a non-specific NO synthase inhibitor) were injected in the left calf with 50 [micro]g murine VEGF165 or vehicle. Serial MRA was performed after injection. Seven days post-injection, mice underwent measurement of either endothelial cell density (by a radiolabelled anti-PECAM immunoassay), regional blood flow measurement (by radiolabelled microsphere deposition) or histological examination.

Results: VEGF greatly increased blood flow to the injected calf muscle (152[+ or -]29 v 10[+ or -]1.8 ml/min/l00 g, p < 0.001), an effect abolished by chronic L-NAME treatment (22[+ or -]3 ml/min/100 g). No increase in blood flow were seen in other regions. VEGF increased capillary density histologically in the injected region, and endothelial cell density in the lower leg was increased by 262% compared with control (p < 0.051, which was unaffected by chronic L-NAME. MRA revealed a time-dependent increase in angiographically detectable vessels proximal to the injected region. These vessels were visible using either blood velocity dependent or independent MRA. The angiographic appearances were unaffected by chronic L-NAME treatment, demonstrating that these vessels hod developed in the absence of increased blood flow.

Conclusion: By using novel techniques, we demonstrate for the first time that…