Stable vascular connections and remodeling require full expression of VE-cadherin in zebrafish embryos.
Stable vascular connections and remodeling require full expression of VE-cadherin in zebrafish embryos.
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DOI：
10.1371/journal.pone.0005772
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发表时间：
2009-06-03
期刊：
影响因子：
3.7
通讯作者：
Dejana E
中科院分区：
文献类型：
--
作者：
Montero-Balaguer M;Swirsding K;Orsenigo F;Cotelli F;Mione M;Dejana E
ve -钙粘蛋白是一种内皮特异性的跨膜蛋白，聚集在粘附连接处，促进同型细胞-细胞粘附。小鼠ve -钙粘蛋白缺失突变由于血管发育改变导致胎儿早期死亡。然而，VE-cadherin的作用机制是复杂的，在小鼠胚胎中，很难确定该蛋白参与血管发育的具体步骤。为了在更合适的模型中研究VE-cadherin在血管系统发育中的作用，我们在斑马鱼中敲低了VE-cadherin编码基因的表达。本文报道的新发现是：1)使用低剂量的morpholinos导致VE-cadherin表达的部分减少，导致血管脆性、头部出血和通透性增加；这是以前没有描述过的，表明表达的蛋白质总量是血管稳定性的重要决定因素；2)高浓度的morpholinos会抑制VE-cadherin的表达，从而阻止血管建立成功的相互接触，因此，血管的发芽活性不会受到抑制。这可能解释了观察到的血管超芽和几条小血管的存在；3)主静脉与心内膜缺乏正确的连接，使心脏与循环系统的其余部分分离。循环回路缺乏闭合以前从未被描述过，这可能解释了一些下游的表型缺陷，如缺乏正确的血管重塑。我们的观察确定了血管发育的几个步骤，其中ve -钙粘蛋白起着至关重要的作用。虽然它似乎不调节维管模式，但它涉及维管连接和发芽活动的抑制。这些过程需要稳定的细胞-细胞连接，而这种连接在缺乏ve -钙粘蛋白的情况下是有缺陷的。值得注意的是，ve -钙粘蛋白表达的部分修饰也阻止了稳定脉管系统的形成。这表明该蛋白的部分内化或功能改变可能强烈影响血管的稳定性和组织。
VE-cadherin is an endothelial specific, transmembrane protein, that clusters at adherens junctions where it promotes homotypic cell-cell adhesion. VE-cadherin null mutation in the mouse results in early fetal lethality due to altered vascular development. However, the mechanism of action of VE-cadherin is complex and, in the mouse embryo, it is difficult to define the specific steps of vascular development in which this protein is involved. In order to study the role VE-cadherin in the development of the vascular system in a more suitable model, we knocked down the expression of the coding gene in zebrafish. The novel findings reported here are: 1) partial reduction of VE-cadherin expression using low doses of morpholinos causes vascular fragility, head hemorrhages and increase in permeability; this has not been described before and suggests that the total amount of the protein expressed is an important determinant of vascular stability; 2) concentrations of morpholinos which abrogate VE-cadherin expression prevent vessels to establish successful reciprocal contacts and, as a consequence, vascular sprouting activity is not inhibited. This likely explains the observed vascular hyper-sprouting and the presence of several small, collapsing vessels; 3) the common cardinal vein lacks a correct connection with the endocardium leaving the heart separated from the rest of the circulatory system. The lack of closure of the circulatory loop has never been described before and may explain some downstream defects of the phenotype such as the lack of a correct vascular remodeling. Our observations identify several steps of vascular development in which VE-cadherin plays an essential role. While it does not appear to regulate vascular patterning it is implicated in vascular connection and inhibition of sprouting activity. These processes require stable cell-cell junctions which are defective in absence of VE-cadherin. Notably, also partial modifications in VE-cadherin expression prevent the formation of a stable vasculature. This suggests that partial internalization or change of function of this protein may strongly affect vascular stability and organization.
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影响因子：
2.7
作者：
Blum, Yannick;Belting, Heinz-Georg;Affolter, Markus
通讯作者：
Affolter, Markus
DOI：
10.1073/pnas.0611510104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Dominguez, Melissa G.;Hughes, Virginia C.;Gale, Nicholas W.
通讯作者：
Gale, Nicholas W.
影响因子：
2.5
作者：
KIMMEL, CB;BALLARD, WW;SCHILLING, TF
通讯作者：
SCHILLING, TF
影响因子：
3.5
作者：
Kawakami, K;Shima, A
通讯作者：
Shima, A
影响因子：
2.1
作者：
Cha, Young Ryun;Weinstein, Brant M.
通讯作者：
Weinstein, Brant M.