CEACAM1: a key regulator of vascular permeability
CEACAM1: a key regulator of vascular permeability
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DOI：
10.1242/jcs.073635
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发表时间：
2010-12-15
影响因子：
4
通讯作者：
Beauchemin, Nicole
中科院分区：
文献类型：
--
作者：
Nouvion, Anne-Laure;Oubaha, Malika;Beauchemin, Nicole
癌胚抗原细胞粘附分子-1（CEACAM 1）是一种免疫球蛋白样细胞表面共受体，在上皮细胞、造血细胞和内皮细胞上表达。CEACAM 1作为粘附分子发挥作用，主要与自身或CEA家族的其他成员结合。我们和其他人以前已经表明，CEACAM 1是在缺血性新血管形成过程中的体内血管完整性的关键。在这里，我们已经破译了CEACAM 1在正常和病理性血管形成中的作用。我们发现Ceacam 1-/-小鼠表现出基础血管通透性的显著增加，这与原代鼠肺内皮细胞（MLEC）中基础Akt和内皮型一氧化氮合酶（eNOS）活化增加有关。此外，MLEC中的CEACAM 1缺失抑制VEGF介导的一氧化氮（NO）产生，这与Ceacam 1-/-小鼠中VEGF依赖性体内渗透性缺陷一致。此外，Ceacam 1基因敲除小鼠表现出肿瘤血管系统通透性增加。最后，我们证明，CEACAM 1是酪氨酸磷酸化VEGF治疗后，在SHP-1和Src依赖的方式，和CEACAM 1的长胞质结构域的关键残基是至关重要的CEACAM 1磷酸化和NO的生产。据我们所知，该数据代表了CEACAM 1与VEGFR 2/Akt/eNOS介导的血管通透性通路之间的功能联系的第一份报告。
Carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) is an immunoglobulin-like cell surface co-receptor expressed on epithelial, hematopoietic and endothelial cells. CEACAM1 functions as an adhesion molecule, mainly binding to itself or other members of the CEA family. We and others have previously shown that CEACAM1 is crucial for in vivo vascular integrity during ischemic neo-vascularization. Here, we have deciphered the roles of CEACAM1 in normal and pathological vascularization. We have found that Ceacam1-/-mice exhibit a significant increase in basal vascular permeability related to increased basal Akt and endothelial nitric oxide synthase (eNOS) activation in primary murine lung endothelial cells (MLECs). Moreover, CEACAM1 deletion in MLECs inhibits VEGF-mediated nitric oxide (NO) production, consistent with defective VEGF-dependent in vivo permeability in Ceacam1-/-mice. In addition, Ceacam1-null mice exhibit increased permeability of tumor vasculature. Finally, we demonstrate that CEACAM1 is tyrosine-phosphorylated upon VEGF treatment in a SHP-1- and Src-dependent manner, and that the key residues of the long cytoplasmic domain of CEACAM1 are crucial for CEACAM1 phosphorylation and NO production. This data represents the first report, to our knowledge, of a functional link between CEACAM1 and the VEGFR2/Akt/eNOS-mediated vascular permeability pathway.