VEGF over-expression in skeletal muscle induces angiogenesis by intussusception rather than sprouting
VEGF over-expression in skeletal muscle induces angiogenesis by intussusception rather than sprouting
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DOI：
10.1007/s10456-012-9304-y
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发表时间：
2013-01-01
期刊：
影响因子：
9.8
通讯作者：
Banfi, Andrea
中科院分区：
文献类型：
--
作者：
Gianni-Barrera, Roberto;Trani, Marianna;Banfi, Andrea
血管内皮生长因子（VEGF）的治疗性过度表达可用于治疗缺血性疾病。然而，VEGF 可以诱导正常或异常的血管生成，具体取决于其在体内每个产生细胞周围的微环境中的剂量，这限制了其临床用途。本文的目标是确定成人骨骼肌中不同剂量 VEGF 过度表达诱导生理血管和异常血管的细胞机制。我们利用一个充分表征的基于细胞的平台来控制骨骼肌中的基因表达。将逆转录病毒转导的成肌细胞克隆群植入免疫缺陷小鼠的肢体肌肉中，以均匀过度表达两种特定的 VEGF(164) 水平，此前已证明这两种水平分别诱导生理性和治疗性或异常血管生成。三种独立且互补的方法（共焦显微镜、血管铸型和连续半薄切片的 3D 重建）表明，在两种 VEGF 剂量下，血管生成均在不发芽的情况下发生，而是通过肠套叠或血管分裂发生。 VEGF 诱导的内皮增殖，但没有尖端细胞形成，导致先前存在的微血管最初均匀增大，随后形成血管内腔内柱，这是肠套叠的标志。这与流量和剪切应力的增加有关，这是肠套叠的有效触发因素。通过临床相关的腺病毒基因治疗载体，在不使用转导细胞的情况下，VEGF 过表达也可诱导类似的不发芽增大过程，随后发生肠套叠。我们的研究结果表明，VEGF 过度表达，在已被证明可诱导功能益处的剂量下，通过肠套叠而不是出芽来诱导骨骼肌中的血管生长。
Therapeutic over-expression of vascular endothelial growth factor (VEGF) can be used to treat ischemic conditions. However, VEGF can induce either normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo, which limits its clinical usefulness. The goal herein was to determine the cellular mechanisms by which physiologic and aberrant vessels are induced by over-expression of different VEGF doses in adult skeletal muscle. We took advantage of a well-characterized cell-based platform for controlled gene expression in skeletal muscle. Clonal populations of retrovirally transduced myoblasts were implanted in limb muscles of immunodeficient mice to homogeneously over-express two specific VEGF(164) levels, previously shown to induce physiologic and therapeutic or aberrant angiogenesis, respectively. Three independent and complementary methods (confocal microscopy, vascular casting and 3D-reconstruction of serial semi-thin sections) showed that, at both VEGF doses, angiogenesis took place without sprouting, but rather by intussusception, or vascular splitting. VEGF-induced endothelial proliferation without tip-cell formation caused an initial homogeneous enlargement of pre-existing microvessels, followed by the formation of intravascular transluminal pillars, hallmarks of intussusception. This was associated with increased flow and shear stress, which are potent triggers of intussusception. A similar process of enlargement without sprouting, followed by intussusception, was also induced by VEGF over-expression through a clinically relevant adenoviral gene therapy vector, without the use of transduced cells. Our findings indicate that VEGF over-expression, at doses that have been shown to induce functional benefit, induces vascular growth in skeletal muscle by intussusception rather than sprouting.