Induction, differentiation, and remodeling of blood vessels after transplantation of Bcl-2-transduced endothelial cells
Induction, differentiation, and remodeling of blood vessels after transplantation of Bcl-2-transduced endothelial cells
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DOI：
10.1073/pnas.0408357102
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发表时间：
2005-01-11
影响因子：
11.1
通讯作者：
Schechner, JS
中科院分区：
文献类型：
--
作者：
Enis, DR;Shepherd, BR;Schechner, JS
含有 Bcl-2 转导的人脐静脉内皮细胞 (Bcl-2-HUVEC) 的胶原蛋白纤连蛋白凝胶植入物可诱导免疫缺陷小鼠形成人内皮细胞 (EC)/鼠血管平滑肌细胞 (VSMC) 嵌合血管。植入后60天对脉管系统进行微丝铸造，显示植入物内高度分支的微血管网络与腹壁循环引起的导管血管连接并诱导其重塑。植入物内约 85% 的血管排列有表达 VEGFR1、VEGFR2 和 Tie-2 但不表达整合素 alpha(v)beta(3) 的 Bcl-2 阳性人类 EC。人 EC 位于结构良好的人层粘连蛋白/IV 胶原蛋白阳性基底膜上，并被表达 SM-α 肌动蛋白、SM 肌球蛋白、SM22α 和钙调蛋白（所有收缩功能标志物）的小鼠 VSMC 包围。透射电子显微镜鉴定出结构良好的 EC-EC 连接、具有收缩性 VSMC 同心层的嵌合小动脉、被周细胞包围的嵌合毛细血管和嵌合小静脉。 Bcl-2-HUVEC 衬里的血管保留 70-kDa FITC-葡聚糖，但不保留 3-kDa 葡聚糖；局部组胺迅速引起 70-kDa FITC-clextran 或印度墨水的泄漏。与皮肤中一样，TNF 仅在小静脉 EC 上诱导 E-选择素和血管细胞粘附分子 1，而细胞间粘附分子 1 在所有人类 EC 上均上调。 Bcl-2-HUVEC 植入物能够在股动脉结扎后植入缺血性小鼠腓肠肌并增加其灌注。这些研究表明，培养的 Bcl-2-HUVEC 在植入体内后可以分化为动脉、静脉和毛细血管样 EC，并诱导局部小鼠血管的动脉重塑。我们的结果支持分化的 EC 移植治疗组织缺血的效用。
Implants of collagen-fibronectin gels containing Bcl-2-transduced human umbilical vein endothelial cells (Bcl-2-HUVECs) induce the formation of human endothelial cell (EC)/murine vascular smooth muscle cell (VSMC) chimeric vessels in immunodeficient mice. Microfil casting of the vasculature 60 d after implantation reveals highly branched microvascular networks within the implants that connect with and induce remodeling of conduit vessels arising from the abdominal wall circulation. Approximately 85% of vessels within the implants are lined by Bcl-2-positive human ECs expressing VEGFR1, VEGFR2, and Tie-2, but not integrin alpha(v)beta(3). The human ECs are seated on a well formed human laminin/collagen IV-positive basement membrane, and are surrounded by mouse VSMCs expressing SM-alpha actin, SM myosin, SM22alpha, and calponin, all markers of contractile function. Transmission electron microscopy identified well formed EC-EC junctions, chimeric arterioles with concentric layers of contractile VSMC, chimeric capillaries surrounded by pericytes, and chimeric venules. Bcl-2-HUVEC-lined vessels retain 70-kDa FITC-dextran, but not 3-kDa dextran; local histamine rapidly induces leak of 70-kDa FITC-clextran or India ink. As in skin, TNF induces E-selectin and vascular cell adhesion molecule 1 only on venular ECs, whereas intercellular adhesion molecule-1 is up-regulated on all human ECs. Bcl-2-HUVEC implants are able to engraft within and increase perfusion of ischemic mouse gastrocnemius muscle after femoral artery ligation. These studies show that cultured Bcl-2-HUVECs can differentiate into arterial, venular, and capillary-like ECs when implanted in vivo, and induce arteriogenic remodeling of the local mouse vessels. Our results support the utility of differentiated EC transplantation to treat tissue ischemia.