Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension
Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension
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DOI：
10.1096/fj.00-0343com
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发表时间：
2001-02-01
期刊：
影响因子：
4.8
通讯作者：
Tuder, RM
中科院分区：
文献类型：
--
作者：
Taraseviciene-Stewart, L;Kasahara, Y;Tuder, RM
严重肺动脉高压通常是一种致命的疾病，我们对其病理生物学的理解一直受到其自然史信息缺乏的阻碍。我们已经证明，在人类严重肺动脉高压中，毛细血管前动脉被增殖的内皮细胞阻塞。血管内皮生长因子（VEGF）及其受体2 （VEGFR-2）参与内皮细胞的正常维持、分化和功能。我们在这里证明，用SU5416阻断VEGFR-2并联合慢性低压缺氧可引起严重的肺动脉高压，并伴有内皮细胞增殖引起的毛细血管前动脉闭塞。激活caspase 3免疫染色和TUNEL结果显示，慢性缺氧su5416治疗的大鼠肺在发生严重肺动脉高压之前和伴随发生严重肺动脉高压，肺内皮细胞明显死亡。广泛性caspase抑制剂Z-Asp-CH2-DCB可阻止血管内肺内皮细胞生长的发展和SU5416与慢性缺氧联合引起的严重肺动脉高压。
Our understanding of the pathobiology of severe pulmonary hypertension, usually a fatal disease, has been hampered by the lack of information of its natural history. We have demonstrated that, in human severe pulmonary hypertension, the precapillary pulmonary arteries show occlusion by proliferated endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR-2) are involved in proper maintenance, differentiation, and function of endothelial cells. We demonstrate here that VEGFR-2 blockade with SU5416 in combination with chronic hypobaric hypoxia causes severe pulmonary hypertension associated with precapillary arterial occlusion by proliferating endothelial cells. Prior to and concomitant with the development of severe pulmonary hypertension, lungs of chronically hypoxic SU5416-treated rats show significant pulmonary endothelial cell death, as demonstrated by activated caspase 3 immunostaining and TUNEL. The broad caspase inhibitor Z-Asp-CH2-DCB prevents the development of intravascular pulmonary endothelial cell growth and severe pulmonary hypertension caused by the combination of SU5416 and chronic hypoxia.