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VASCULAR BIOLOGY

Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2

Departments of ¹Pediatrics, ²Ophthalmology and Visual Sciences, and ³Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Submitted 15 December 2007 ; accepted in final form 11 April 2008

Apoptosis plays a critical role during development and in the maintenance of the vascular system. B-cell leukemia lymphoma 2 (bcl-2) protects endothelial cells (EC) from apoptosis in response to a variety of stimuli. Previous work from this laboratory demonstrated attenuation of postnatal retinal vascular development and retinal neovascularization during oxygen-induced ischemic retinopathy in bcl-2-deficient (bcl-2^–/–) mice. To gain further insight into the function of bcl-2 in the endothelium, we isolated retinal EC from bcl-2^+/+ and bcl-2^–/– mice. Retinal EC lacking bcl-2 demonstrated reduced cell migration, tenascin-C expression, and adhesion to vitronectin and fibronectin. The bcl-2^–/– retinal EC also failed to undergo capillary morphogenesis in Matrigel. In addition, using an ex vivo angiogenesis assay, we observed reduced sprouting from aortic rings grown in culture from bcl-2^–/– mice compared with bcl-2^+/+ mice. Furthermore, reexpression of bcl-2 was sufficient to restore migration and capillary morphogenesis defects observed in bcl-2^–/– retinal EC. Mechanistically, bcl-2^–/– cells expressed significantly less endothelial nitric oxide synthase, an important downstream effecter of proangiogenic signaling. This may be attributed to increased oxidative stress in the absence of bcl-2. In fact, incubation of retinal EC or aortic rings from bcl-2^–/– mice with the antioxidant N-acetylcysteine rescued their capillary morphogenesis and sprouting defects. Thus, bcl-2-mediated cellular functions play important roles not only in survival but also in proangiogenic phenotype of EC with a significant impact on vascular development and angiogenesis.

angiogenesis; apoptosis; endothelial nitric oxide; oxidative stress