Blood flow reprograms lymphatic vessels to blood vessels
Blood flow reprograms lymphatic vessels to blood vessels
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DOI：
10.1172/jci57513
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发表时间：
2012-06-01
影响因子：
15.9
通讯作者：
Kahn, Mark L.
中科院分区：
文献类型：
--
作者：
Chen, Chiu-Yu;Bertozzi, Cara;Kahn, Mark L.
人类血管畸形由于血流和血管血液动力学力的变化而引起疾病。虽然许多人类血管畸形形成的基因突变是已知的，但异常血流随后影响血管遗传程序和自然史的程度却不清楚。含SH2结构域的76 kDa白细胞蛋白（SLP76）的缺失导致血管畸形，该畸形在小鼠出生后引导血流通过肠系膜淋巴管。成熟Slp 76缺失小鼠先天性淋巴管位置的肠系膜血管缺乏淋巴管身份，并表达血管身份标记。遗传谱系追踪表明，这种血管身份的变化是淋巴管内皮细胞重编程的结果，而不是被血液内皮细胞取代。在没有显著血流的情况下，淋巴管暴露于血液中不会改变体内血管的身份，但暴露于类似水平的切应力的淋巴管内皮细胞在体外迅速失去PROX1（一种淋巴管命运特异性转录因子）的表达。这些发现表明，血流可以将淋巴管转化为血管，表明血流动力学可能会在与异常血流相关的心血管疾病中重新编程内皮和血管特性。
Human vascular malformations cause disease as a result of changes in blood flow and vascular hemodynamic forces. Although the genetic mutations that underlie the formation of many human vascular malformations are known, the extent to which abnormal blood flow can subsequently influence the vascular genetic program and natural history is not. Loss of the SH2 domain-containing leukocyte protein of 76 kDa (SLP76) resulted in a vascular malformation that directed blood flow through mesenteric lymphatic vessels after birth in mice. Mesenteric vessels in the position of the congenital lymphatic in mature Slp76-null mice lacked lymphatic identity and expressed a marker of blood vessel identity. Genetic lineage tracing demonstrated that this change in vessel identity was the result of lymphatic endothelial cell reprogramming rather than replacement by blood endothelial cells. Exposure of lymphatic vessels to blood in the absence of significant flow did not alter vessel identity in vivo, but lymphatic endothelial cells exposed to similar levels of shear stress ex vivo rapidly lost expression of PROX1, a lymphatic fate-specifying transcription factor. These findings reveal that blood flow can convert lymphatic vessels to blood vessels, demonstrating that hemodynamic forces may reprogram endothelial and vessel identity in cardiovascular diseases associated with abnormal flow.