Terrell G E, Swain J L
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Matrix. 1991 Apr;11(2):108-14. doi: 10.1016/s0934-8832(11)80214-3.
Vascular growth factors are categorized as either primary or secondary angiogenic factors. Primary angiogenic agents such as fibroblast growth factors, not only induce the complete angiogenic response, but also stimulate the individual components of vascular growth. Secondary angiogenic agents can induce vascular growth, but they do not act through the direct stimulation of endothelial proliferation, migration, and protease production. Since fibroblast growth factors are known to bind to components of the extracellular matrix, we assessed whether secondary agents act through liberating growth factors from matrix storage sites. The study utilized L6 skeletal myoblasts in culture, which we demonstrated were capable of synthesizing extracellular matrix containing heparin binding endothelial mitogens. The heparin-binding mitogenic activity accumulated in a time-dependent fashion, and matrix extracts contained a protein with immunologic identity to acidic fibroblast growth factor. The ability of secondary angiogenic agents and related compounds including adenosine, inosine, hypoxanthine, nicotinamide, lactic acid, phorbol esters, prostaglandin E2, and copper (at concentrations of 1 microM and 1 mM) to release heparin binding mitogenic activity from the matrix was evaluated. The results demonstrate that although heparin is capable of releasing heparin-binding growth factors from extracellular matrix storage sites in a dose dependent fashion, none of the known secondary angiogenesis factors are capable of functioning in a similar fashion. Thus these secondary angiogenic factors do not appear to exert their effect through increasing the bioavailability of preformed heparin-binding growth factors sequestered in the extracellular matrix. The mechanism(s) whereby these agents induce vascular growth remains to be elucidated.
血管生长因子可分为原发性或继发性血管生成因子。原发性血管生成因子，如成纤维细胞生长因子，不仅能诱导完整的血管生成反应，还能刺激血管生长的各个组成部分。继发性血管生成因子可诱导血管生长，但它们并非通过直接刺激内皮细胞增殖、迁移和蛋白酶产生来发挥作用。由于已知成纤维细胞生长因子能与细胞外基质成分结合，我们评估了继发性因子是否通过从基质储存部位释放生长因子来发挥作用。该研究利用培养的L6骨骼肌成肌细胞，我们证明这些细胞能够合成含有肝素结合内皮细胞促有丝分裂原的细胞外基质。肝素结合促有丝分裂活性呈时间依赖性积累，并且基质提取物中含有一种与酸性成纤维细胞生长因子具有免疫同源性的蛋白质。我们评估了继发性血管生成因子及相关化合物，包括腺苷、肌苷、次黄嘌呤、烟酰胺、乳酸、佛波酯、前列腺素E2和铜（浓度为1微摩尔和1毫摩尔）从基质中释放肝素结合促有丝分裂活性的能力。结果表明，尽管肝素能够以剂量依赖的方式从细胞外基质储存部位释放肝素结合生长因子，但已知的继发性血管生成因子均不能以类似方式发挥作用。因此，这些继发性血管生成因子似乎并非通过增加细胞外基质中预先存在的肝素结合生长因子的生物利用度来发挥作用。这些因子诱导血管生长的机制仍有待阐明。
