title: VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature.
abstract: Unlike during development, blood vessels in the adult 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 1-3 wk. Blood vessels were assessed using 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 wk after cessation of treatment for 1 wk. Our findings of VEGF dependency of normal fenestrated capillaries and rapid regrowth after regression demonstrate the plasticity of the adult microvasculature.
authors.affiliation: Cardiovascular Research Institute, and Dept. of Anatomy, Univ. of California, 513 Parnassus Ave., San Francisco, CA 94143-0452, USA.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kamba
authors.forename: Betty Y Y
authors.initials: BY
authors.lastname: Tam
authors.forename: Hiroya
authors.initials: H
authors.lastname: Hashizume
authors.forename: Amy
authors.initials: A
authors.lastname: Haskell
authors.forename: Barbara
authors.initials: B
authors.lastname: Sennino
authors.forename: Michael R
authors.initials: MR
authors.lastname: Mancuso
authors.forename: Scott M
authors.initials: SM
authors.lastname: Norberg
authors.forename: Shaun M
authors.initials: SM
authors.lastname: O'Brien
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Davis
authors.forename: Lori C
authors.initials: LC
authors.lastname: Gowen
authors.forename: Keith D
authors.initials: KD
authors.lastname: Anderson
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: Shuji
authors.initials: S
authors.lastname: Joho
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Springer
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000375:Aging; D000818:Animals; D000077784:Axitinib; D001794:Blood Pressure; D002196:Capillaries / Q000502:physiology* / Q000648:ultrastructure; D018827:Carcinoma, Lewis Lung / Q000098:blood supply; D005951:Glucose Tolerance Test; D006321:Heart / Q000502:physiology; D007093:Imidazoles; D007191:Indazoles / Q000494:pharmacology; D007515:Islets of Langerhans / Q000098:blood supply; D007668:Kidney / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000098:blood supply; D010641:Phenotype; D012016:Reference Values; D012038:Regeneration; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D007093:Imidazoles; D007191:Indazoles; D042461:Vascular Endothelial Growth Factor A; D000077784:Axitinib; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2