VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature
VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature
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DOI：
10.1152/ajpheart.00133.2005
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发表时间：
2006-02-01
影响因子：
4.8
通讯作者：
McDonald, DM
中科院分区：
文献类型：
--
作者：
Kamba, T;Tam, BYY;McDonald, DM
与发育期间不同的是，成年人的血管通常被认为不需要血管内皮生长因子来发挥正常功能。然而，血管内皮生长因子是许多肿瘤血管的生存因子，有线索表明，一些正常的血管可能也依赖于血管内皮生长因子。在这项研究中，我们试图确定成年小鼠的哪些血管床(如果有的话)依赖血管内皮生长因子生存。小鼠接受小分子血管内皮生长因子受体(VEGFR)酪氨酸激酶抑制剂或可溶性VEGFRs治疗1-3wk。用免疫组织化学或扫描或透射电子显微镜对血管进行评估。在对血管内皮生长因子抑制后的17个正常器官的研究中，我们发现在胰岛、甲状腺、肾上腺皮质、垂体、脉络丛、小肠绒毛和附睾脂肪组织中有显著的毛细血管退缩。RIP-Tag2转基因小鼠的肿瘤和Lewis肺癌的退化量随剂量的变化而不同，在甲状腺中最高可达68%，但在正常器官中的退行性较小。血管内皮生长因子依赖的毛细血管有窗孔，高水平表达VEGFR-2和VEGFR-3，周细胞覆盖正常。病变器官中存活的毛细血管开窗较少，VEGFR表达较少。所有小鼠看起来都很健康，但伴随着一些抑制血管内皮生长因子的方案，出现了明显的生理变化，包括更有效的血糖处理。值得注意的是，大多数甲状腺毛细血管在停止治疗1周后2周内恢复生长。我们对正常有窗毛细血管的血管内皮生长因子依赖性和回归后的快速再生的研究结果证明了成人微血管系统的可塑性。
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.