EVIDENCE THAT NITRIC-OXIDE IS AN ENDOGENOUS ANTIANGIOGENIC MEDIATOR
EVIDENCE THAT NITRIC-OXIDE IS AN ENDOGENOUS ANTIANGIOGENIC MEDIATOR
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DOI：
10.1111/j.1476-5381.1994.tb14822.x
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发表时间：
1994-03-01
影响因子：
7.3
通讯作者：
MARAGOUDAKIS, ME
中科院分区：
文献类型：
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作者：
PIPILISYNETOS, E;SAKKOULA, E;MARAGOUDAKIS, ME
1在鸡胚绒毛尿囊膜体内系统和基质细胞管形成实验中检测一氧化氮(NO)对血管生成的调节。2自发释放NO的硝普钠(SNP)(0.37~28nmoL/盘)可剂量依赖性地抑制体内CAM的血管生成，并完全逆转α-凝血酶(6.7nmoL/盘)和蛋白激酶C激活剂4-β-佛波酯-12-肉豆蔻酸酯-13-乙酸酯(0.97nmoL/盘)的血管生成作用。此外，SNP(28×10(-6)M)可刺激体外培养的CAM释放鸟苷3‘-5’-环一磷酸(CGMP)。3在体外血管形成实验中，硝普钠(1-3×10(-6)M)和细胞通透性环状GMP类似物(BR-cGMP(0.3-1.0×10(-3)M)均可减少血管形成。4一氧化氮合酶抑制剂L(3.8~102nmol/片)和N-G-硝基L精氨酸甲酯(L-NAME)(1.3~34.2nmol/片)可促进体内血管生成，并呈剂量依赖关系，D-NMMA和D-NAME对该系统的血管生成无影响。5 L精氨酸(10.9nmol/只)虽有一定的抗血管生成作用，但可阻断L(34.2nmol/只)和L精氨酸(3.8nmol/只)的促血管生成作用。6地塞米松是一氧化氮合酶诱导的阻断剂，当浓度为0.2~116.1 nmol/盘时，可促进血管生成，而在348.4~1161nmol/盘时，则抑制这一过程。地塞米松38.7nmol/片与L-NAME(9.3nmol/片)联合使用，可增强前者的血管生成作用。因此，结构性和诱导型NO合酶都可能参与了NO介导的血管生成抑制。7防止NO破坏的超氧化物歧化酶(SOD)在300IU./Disk时，其本身在CAM中有适度的抗血管生成作用。此外，超氧化物歧化酶可抑制α-凝血酶(6.7nmoL/Disc)和PMA(0.97nmoL/Disc)刺激CAM血管生成。8上述结果提示，NO可能是一种具有重要病理生理意义的内源性抗血管生成分子。
1 The involvement of nitric oxide (NO) in the regulation of angiogenesis was examined in the in vivo system of the chorioallantoic membrane (CAM) of the chick embryo and in the matrigel tube formation assay. 2 Sodium nitroprusside (SNP) (0.37-28 nmol/disc), which releases NO spontaneously, caused a dose-dependent inhibition of angiogenesis in the CAM in vivo and reversed completely the angiogenic effects of alpha-thrombin (6.7 nmol/disc) and the protein kinase C (PKC) activator 4-beta-phorbol-12-myristate-13-acetate (PMA) (0.97 nmol/disc). In addition, SNP (28 x 10(-6) M) stimulated the release of guanosine 3'-5'-cyclic monophosphate (cyclic GMP) from the CAM in vitro. 3 In the matrigel tube formation assay, an in vitro assay of angiogenesis, both SNP (1-3 x 10(-6) M) and the cell permeable cyclic GMP analogue, Br-cGMP (0.3-1.0 x 10(-3) M) reduced tube formation. 4 The inhibitors of NO synthase, N-G-monomethyl-L-arginine (L-NMMA) (3.8-102 nmol/disc) and N-G-nitro-L-arginine methylester (L-NAME) (1.3-34.2 nmol/disc) stimulated angiogenesis in the CAM in vivo, in a dose-dependent fashion, D-NMMA and D-NAME on the other hand had no effect on angiogenesis in this system. 5 L-Arginine (10.9 nmol/disc), although it had a modest antiangiogenic effect by itself, was capable of abolishing the angiogenic effects of L-NMMA (34.2 nmol/disc) and of L-NAME (3.8 nmol/disc). 6 Dexamethasone, an inhibitor of the induction of NO synthase, at 0.2-116.1 nmol/disc, stimulated angiogenesis in the CAM, whereas at 348.4-1161 nmol/disc it inhibited this process. Combination of 38.7 nmol/disc dexamethasone with L-NAME (9.3 nmol/disc) resulted in a potentiation of the angiogenic effect of the former. It appears therefore that both the constitutive and the inducible NO synthase may contribute to the NO-mediated inhibition of angiogenesis. 7 Superoxide dismutase (SOD), which prevents the destruction of NO, at 300 i.u./disc had a modest antiangiogenic effect in the CAM, by itself. In addition, SOD, prevented alpha-thrombin (6.7 nmol/disc) and PMA (0.97 nmol/disc) from stimulating angiogenesis in the CAM. 8 These results suggest that NO may be an endogenous antiangiogenic molecule of pathophysiological importance.