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1 Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco, San Francisco, California, USA
2 Hematology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
3 Regeneron Pharmaceuticals, Tarrytown, New York, USA
4 Cardiology Division, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
* To whom correspondence should be addressed. E-mail: dmcd{at}itsa.ucsf.edu.
Blood vessels in the adult, unlike during development, are generally thought not to require VEGF for normal function. However, VEGF is a survival factor for many tumor vessels, and there are clues that some normal blood vessels may also depend on VEGF. In this study, we sought to identify which, if any, vascular beds in adult mice depend on VEGF for survival. Mice were treated with a small molecule VEGF receptor (VEGFR) tyrosine kinase inhibitor or soluble VEGFRs for 1 to 3 weeks. Blood vessels were assessed by immunohistochemistry or scanning or transmission electron microscopy. In a study of 17 normal organs after VEGF inhibition, we found significant capillary regression in pancreatic islets, thyroid, adrenal cortex, pituitary, choroid plexus, small intestinal villi, and epididymal adipose tissue. The amount of regression was dose-dependent and varied from organ to organ, with a maximum of 68% in thyroid, but was less in normal organs than in tumors in RIP-Tag2 transgenic mice or in Lewis lung carcinoma. VEGF-dependent capillaries were fenestrated, expressed high levels of both VEGFR-2 and VEGFR-3, and had normal pericyte coverage. Surviving capillaries in affected organs had fewer fenestrations and less VEGFR expression. All mice appeared healthy, but distinct physiological changes, including more efficient blood glucose handling, accompanied some regimens of VEGF inhibition. Strikingly, most capillaries in the thyroid grew back within 2 weeks after cessation of treatment for one week. Our findings of VEGF-dependency of normal fenestrated capillaries and rapid regrowth after regression illustrate the plasticity of the adult microvasculature.
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