Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun C O, Buerk D G, Huang P L, Jain R K
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2604-9. doi: 10.1073/pnas.041359198.
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) > or = WT with l-NIL or iNOS(-/-) > eNOS(-/-) > or = 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.
一氧化氮（NO）在血管内皮生长因子（VEGF）诱导的血管生成和血管通透性增加过程中起着关键作用。然而，不同的一氧化氮合酶（NOS）同工型对这些过程的相对贡献尚不清楚。在此，我们评估了内皮型一氧化氮合酶和诱导型一氧化氮合酶（分别为eNOS和iNOS）对VEGF诱导的血管生成血管的生成和通透性的相对贡献。通过使用eNOS基因缺陷小鼠评估eNOS的贡献，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基因缺陷小鼠评估iNOS的贡献。将I型胶原蛋白凝胶置于小鼠颅窗中，用VEGF诱导血管生成。血管生成、血管直径、血流速度和血管通透性与用微电极测量的NO水平成正比：野生型（WT）≥WT加l-NIL或iNOS基因敲除小鼠＞eNOS基因敲除小鼠≥eNOS基因敲除小鼠加l-NIL。还通过使用eNOS和iNOS基因缺陷小鼠确定了NOS在VEGF诱导的静止血管急性血管通透性增加中的作用。VEGF灌注显著增加了WT和iNOS基因敲除小鼠的通透性，但未增加eNOS基因敲除小鼠的通透性。这些发现表明，eNOS在VEGF诱导的血管生成和血管通透性中起主要作用。因此，选择性调节eNOS活性是改变体内血管生成和血管通透性的一种有前景的策略。
