Pettersson A, Nagy J A, Brown L F, Sundberg C, Morgan E, Jungles S, Carter R, Krieger J E, Manseau E J, Harvey V S, Eckelhoefer I A, Feng D, Dvorak A M, Mulligan R C, Dvorak H F
Department of Pathology, Children's Hospital, and Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts 02215, USA.
Lab Invest. 2000 Jan;80(1):99-115. doi: 10.1038/labinvest.3780013.
Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is an angiogenic cytokine with potential for the treatment of tissue ischemia. To investigate the properties of the new blood vessels induced by VPF/VEGF, we injected an adenoviral vector engineered to express murine VPF/VEGF164 into several normal tissues of adult nude mice or rats. A dose-dependent angiogenic response was induced in all tissues studied but was more intense and persisted longer (months) in skin and fat than in heart or skeletal muscle (< or =3 weeks). The initial response (within 18 hours) was identical in all tissues studied and was characterized by microvascular hyperpermeability, edema, deposition of an extravascular fibrin gel, and the formation of enlarged, thin-walled pericyte-poor vessels ("mother" vessels). Mother vessels developed from preexisting microvessels after pericyte detachment and basement membrane degradation. Mother vessels were transient structures that evolved variably in different tissues into smaller daughter vessels, disorganized vessel tangles (glomeruloid bodies), and medium-sized muscular arteries and veins. Vascular structures closely resembling mother vessels and each mother vessel derivative have been observed in benign and malignant tumors, in other examples of pathological and physiological angiogenesis, and in vascular malformations. Together these data suggest that VPF/VEGF has a role in the pathogenesis of these entities. They also indicate that the angiogenic response induced by VPF/VEGF is heterogeneous and tissue specific. Finally, the muscular vessels that developed from mother vessels in skin and perimuscle fat have the structure of collaterals and could be useful clinically in the relief of tissue ischemia.
血管通透因子/血管内皮生长因子（VPF/VEGF）是一种具有治疗组织缺血潜力的血管生成细胞因子。为了研究由VPF/VEGF诱导生成的新生血管的特性，我们将一种经过基因工程改造以表达鼠源VPF/VEGF164的腺病毒载体注射到成年裸鼠或大鼠的多个正常组织中。在所研究的所有组织中均诱导出了剂量依赖性的血管生成反应，但在皮肤和脂肪组织中的反应更为强烈且持续时间更长（数月），而在心脏或骨骼肌中则较短（≤3周）。在所有研究的组织中，最初的反应（18小时内）是相同的，其特征为微血管通透性增加、水肿、血管外纤维蛋白凝胶沉积以及形成扩张的、薄壁且周细胞较少的血管（“母”血管）。母血管是在周细胞脱离和基底膜降解后由预先存在的微血管发育而来。母血管是短暂性结构，在不同组织中会以不同方式演变成较小的子血管、无序的血管缠结（类球体）以及中型肌性动静脉。在良性和恶性肿瘤、其他病理性和生理性血管生成的例子以及血管畸形中，均观察到了与母血管及其各种衍生物极为相似的血管结构。这些数据共同表明，VPF/VEGF在这些病变的发病机制中发挥作用。它们还表明，VPF/VEGF诱导的血管生成反应具有异质性且具有组织特异性。最后，在皮肤和肌周脂肪中由母血管发育而来的肌性血管具有侧支血管的结构，在临床上可能有助于缓解组织缺血。
