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Molecular and Cellular Biology, November 2007, p. 7683-7692, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00577-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Essential Role of Endothelial Smad4 in Vascular Remodeling and Integrity{triangledown} ,{dagger}

Yu Lan,1 Bing Liu,2 Huiyu Yao,2 Fangfei Li,1 Tujun Weng,1 Guan Yang,1 Wenlong Li,1 Xuan Cheng,1 Ning Mao,2 and Xiao Yang1*

Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071,1 Department of Cell Biology, Institute of Basic Medical Sciences, Beijing 100850, People's Republic of China2

Received 2 April 2007/ Returned for modification 30 May 2007/ Accepted 13 August 2007

New blood vessels are formed through the assembly or sprouting of endothelial cells (ECs) and become stabilized by the formation of perivascular matrix and the association with supporting mural cells. To investigate the role of endothelial Smad4 in vascular development, we deleted the Smad4 gene specifically in ECs using the Cre-LoxP system. EC-specific Smad4 mutant mice died at embryonic day 10.5 due to cardiovascular defects, including attenuated vessels sprouting and remodeling, collapsed dorsal aortas, enlarged hearts with reduced trabeculae, and failed endocardial cushion formation. Noticeably, Smad4-deficient ECs demonstrated an intrinsic defect in tube formation in vitro. Furthermore, the mutant vascular ECs dissociated away from the surrounding cells and suffered from impaired development of vascular smooth muscle cells. The disturbed vascular integrity and maturation was associated with aberrant expression of angiopoietins and a gap junction component, connexin43. Collectively, we have provided direct functional evidence that Smad4 activity in the developing ECs is essential for blood vessel remodeling, maturation, and integrity.

* Corresponding author. Mailing address: Institute of Biotechnology, 20 Dongdajie, Beijing 100071, People's Republic of China. Phone and fax: 86-10-63895937. E-mail: yangx{at}nic.bmi.ac.cn

{triangledown} Published ahead of print on 27 August 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2007, p. 7683-7692, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00577-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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