Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability
Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability
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DOI：
10.1073/pnas.041359198
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发表时间：
2001-02-27
影响因子：
11.1
通讯作者：
Jain, RK
中科院分区：
文献类型：
--
作者：
Fukumura, D;Gohongi, T;Jain, RK
一氧化氮（Nitric oxide，NO）在血管内皮生长因子（vascular endothelial growth factor，VEGF）诱导的血管新生和血管通透性增高中起重要作用，但不同的NO合酶（nitric oxide synthase，NOS）亚型在这些过程中的作用尚不清楚。在这里，我们评估了内皮型和诱导型NOS（eNOS和iNOS，分别）血管生成和VEGF诱导的血管生成血管的渗透性的相对贡献。通过使用eNOS缺陷型小鼠评估eNOS的贡献，并且通过使用选择性抑制剂[L-N-6-（1-亚氨基乙基）赖氨酸，L-NIL]和iNOS缺陷型小鼠评估iNOS的贡献。VEGF诱导血管生成的I型胶原凝胶放置在小鼠颅窗。血管生成、血管直径、血流速率和血管渗透性与用微电极测量的NO水平成比例：野生型（WT）大于或等于WT与L-NIL或iNOS（-/-）> eNOS（-/-）大于或等于eNOS（-/-）与L-NIL。NOS在静止血管中VEGF诱导的急性血管通透性增加中的作用也通过使用eNOS和iNOS缺陷小鼠来确定。VEGF灌流显著增加WT和iNOS-/-小鼠的通透性，但在eNOS（-/-）小鼠中不增加。这些结果表明，eNOS在VEGF诱导的血管生成和血管通透性中起着主导作用。因此，eNOS活性的选择性调节是一个有前途的策略，改变血管生成和血管通透性在体内。
Nitric oxide (NO) plays a critical role in vascular endothelial growth factor (VEGF)-induced angiogenesis and vascular hyperpermeability, However, the relative contribution of different NO synthase (NOS) isoforms to these processes is not known. Here, we evaluated the relative contributions of endothelial and inducible NOS (eNOS and iNOS, respectively) to angiogenesis and permeability of VEGF-induced angiogenic vessels. The contribution of eNOS was assessed by using an eNOS-deficient mouse, and iNOS contribution was assessed by using a selective inhibitor [L-N-6-(1-iminoethyl) lysine, L-NIL] and an iNOS-deficient mouse. Angiogenesis was induced by VEGF in type I collagen gels placed in the mouse cranial window. Angiogenesis, vessel diameter, blood flow rate, and vascular permeability were proportional to NO levels measured with microelectrodes: Wild-type (WT) greater than or equal to WT with L-NIL or iNOS(-/-) > eNOS(-/-) greater than or equal to eNOS(-/-) with L-NIL. The role of NOS in VEGF-induced acute vascular permeability increase in quiescent vessels also was determined by using eNOS- and iNOS-deficient mice. VEGF superfusion significantly increased permeability in both WT and iNOS-/- mice but not in eNOS(-/-) mice. These findings suggest that eNOS plays a predominant role in VEGF-induced angiogenesis and vascular permeability. Thus, selective modulation of eNOS activity is a promising strategy for altering angiogenesis and vascular permeability in vivo.