SM22alpha-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis.
SM22alpha-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis.
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DOI：
10.1242/dev.017863
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发表时间：
2008-09
期刊：
影响因子：
--
通讯作者：
Rabinovitch M
中科院分区：
文献类型：
--
作者：
El-Bizri N;Guignabert C;Wang L;Cheng A;Stankunas K;Chang CP;Mishina Y;Rabinovitch M
骨形态发生蛋白受体1a(BMPR1A)在肺动脉高压患者肺血管中的表达减弱，但这种异常对功能的影响尚不清楚。因此，我们通过用表达R26R的BMPR1A(Bmpr1aflox)的loxP等位基因与Sm22α-Cre小鼠杂交来去除心肌细胞和血管平滑肌细胞中的BMPR1a。Sm22α-Cre；R26R；Bmpr1aflox/FLOX小鼠在胚胎第11天(E11)后不久死亡，出现大量血管和心包出血，脑部发育受损。在E10.5，Sm22α-Cre；R26R；Bmpr1aflox/Flox胚胎显示心肌变薄，细胞增殖降低。这些胚胎也有严重的主动脉和大血管扩张，SMC投资受损，这也与增殖减少有关。Sm22α-Cre；R26R；Bmpr1aflox/FLOX小鼠表现出端脑塌陷，并伴有脑微血管的清除障碍，其中观察到的细胞凋亡减少。在E9.5和E10.5SM22α-Cre、R26R和Bmpr1aflox/FLOX胚胎中，基质金属蛋白酶-2和-9的转录和蛋白水平分别降低。通过RNA干扰抑制人肺动脉SMC中BMPR1A的表达，可降低MMP2和MMP9的活性，减弱血清诱导的增殖，并损害PDGF-BB导向的迁移。MMP2或MMP9的RNA干扰概括了这些异常，支持BMP信号和MMP2表达之间的功能相互作用。在人脑微血管周细胞中，BMPR1A的敲除降低了基质金属蛋白酶-2的活性，而BMPR1A或基质金属蛋白酶-2的敲除都导致了对细胞凋亡的抵抗。因此，通过降低基质金属蛋白酶-2和/或基质金属蛋白酶-9的活性，BMPR1A的缺失可以解释血管扩张和脑微血管的持续存在，从而导致脑组织器官发生受损。
Expression of bone morphogenetic protein receptor 1a (Bmpr1a) is attenuated in lung vessels of patients with pulmonary arterial hypertension, but the functional impact of this abnormality is unknown. We therefore ablated Bmpr1a in cardiomyocytes and vascular smooth muscle cells (VSMC) by breeding mice with a loxP allele of Bmpr1a (Bmpr1aflox) expressing R26R with SM22α-Cre mice. SM22α-Cre;R26R;Bmpr1aflox/flox mice died soon after embryonic day 11 (E11) with massive vascular and pericardial hemorrhage and impaired brain development. At E10.5, SM22α-Cre;R26R;Bmpr1aflox/flox embryos showed thinning of the myocardium associated with reduced cell proliferation. These embryos also had severe dilatation of the aorta and large vessels with impaired investment of SMC that was also related to reduced proliferation. SM22α-Cre;R26R;Bmpr1aflox/flox mice showed collapsed telencephalon in association with impaired clearing of brain microvessels in areas where reduced apoptosis was observed. Transcript and protein levels of matrix metalloproteinase (MMP)-2 and -9 were reduced in E9.5 and E10.5 SM22α-Cre;R26R;Bmpr1aflox/flox embryos, respectively. Knock-down of Bmpr1a by RNA interference in human pulmonary artery SMC reduced MMP-2 and MMP-9 activity, attenuated serum-induced proliferation, and impaired PDGF-BB-directed migration. RNA interference of MMP-2 or MMP-9 recapitulated these abnormalities, supporting a functional interaction between BMP signaling and MMP expression. In human brain microvascular pericytes, knock-down of Bmpr1a reduced MMP-2 activity and knock-down of either Bmpr1a or MMP-2 caused resistance to apoptosis. Thus loss of Bmpr1a, by decreasing MMP-2 and/or MMP-9 activity, can account for vascular dilatation and persistence of brain microvessels leading to impaired organogenesis documented in the brain.
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DOI：
10.1083/jcb.139.1.279
发表时间：
1997-10-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jones PL;Crack J;Rabinovitch M
通讯作者：
Rabinovitch M
影响因子：
158.5
作者：
Du, Lingling;Sullivan, Christopher C.;Thistlethwaite, Patricia A.
通讯作者：
Thistlethwaite, Patricia A.
影响因子：
24
作者：
Humbert, M;Morrell, NW;Rabinovitch, M
通讯作者：
Rabinovitch, M
影响因子：
2.7
作者：
Beppu, H;Kawabata, M;Miyazono, K
通讯作者：
Miyazono, K
DOI：
10.1073/pnas.042390499
发表时间：
2002-03-05
影响因子：
11.1
作者：
Gaussin, V;Van de Putte, T;Schneider, MD
通讯作者：
Schneider, MD