Identification of a putative microvascular oxygen sensor
Identification of a putative microvascular oxygen sensor
复制标题
DOI：
10.1161/01.res.79.1.54
复制
发表时间：
1996-07-01
影响因子：
20.1
通讯作者：
Roman, RJ
中科院分区：
文献类型：
--
作者：
Harder, DR;Narayanan, J;Roman, RJ
血管对血液和组织中氧含量变化的反应是一种高度适应性的生理反应，其功能是使组织氧供应与代谢需求相匹配。定义能够感知 PO2 生理相关变化并调整血管直径的细胞机制对于我们理解这一过程至关重要。 omega-羟化酶 4A 家族的细胞色素 P450 (P450) 酶定位于大鼠的肾微血管、肾皮质和横纹肌微血管床（提睾肌）。在分子氧存在的情况下，这种 P450 酶催化花生四烯酸 (AA) 形成 20-HETE。先前的研究表明，20-HETE 能有效收缩肾动脉和脑动脉和小动脉。本研究表明 20-HETE 也能收缩横纹肌小动脉。在完整的肾微血管和富集的肾皮质微粒体酶制剂中，20-HETE 的形成在 20 至 140 mm Hg 之间线性依赖于 PO2。当与 AA 一起孵育时，提睾肌组织匀浆产生 20-氧 HETE。他们还表达了 P450 4A 酶的信息，如 Southern 和 Western 印迹所确定的。给予 17-十八氰酸 (17-ODYA)（一种 P450 4A 抑制剂）可减弱因灌注液 PO2 从约 3 至 5 mm Hg 升高至约 35 mm Hg 引起的三级提睾小动脉的收缩。 17-ODYA 对基础血管张力或提睾小动脉对血管活性化合物的反应没有影响。这些结果表明至少两个微血管床的脉管系统和实质中存在 P450 omega-羟化酶活性和 20-HETE 形成。我们的数据表明，4A 家族的 P450 酶有潜力在哺乳动物微循环床中充当氧传感器，并通过以氧依赖性方式产生 20-HETE 来调节小动脉口径。
The vascular response to changes in oxygen levels in the blood and tissue is a highly adaptive physiological response that functions to match tissue oxygen supply to metabolic demand. Defining the cellular mechanisms that can sense physiologically relevant changes in PO2 and adjust vascular diameter are vital to our understanding of this process. A cytochrome P450 (P450) enzyme of the 4A family of omega-hydroxylases was localized in renal microvessels, renal cortex, and a striated muscle microvascular bed (cremaster) of the rat. In the presence of molecular oxygen, this P450 enzyme catalyzes formation of 20-HETE from arachidonic acid (AA). Prior studies have shown that 20-HETE potently contracts renal and cerebral arteries and arterioles. The present study demonstrates that 20-HETE constricts striated muscle arterioles as well. In both intact renal microvessels and enriched renal cortical microsomal enzyme preparations, the formation of 20-HETE was linearly dependent on PO2 between 20 and 140 mm Hg. Homogenates of cremaster tissue produced 20-oxygen HETE when incubated with AA. They also expressed message for P450 4A enzyme, as determined by Southern and Western blots. Administration of 17-octadecynoic acid (17-ODYA), which is a P450 4A inhibitor, attenuated the constriction of third-order cremasteric arterioles in response to elevation of superfusion solution PO2 from approximate to 3 to 5 mm Hg to approximate to 35 mm Hg. 17-ODYA had no effect on basal vascular tone or response of cremaster arterioles to vasoactive compounds. These results demonstrate the existence of P450 omega-hydroxylase activity and 20-HETE formation in the vasculature and parenchyma of at least two microvascular beds. Our data suggest that a P450 enzyme of the 4A family has the potential to function as an oxygen sensor in mammalian microcirculatory beds and to regulate arteriolar caliber by generating 20-HETE in an oxygen-dependent manner.