Essential role of endothelial Smad4 in vascular remodeling and integrity.
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.
Lan
Yu
Y
Genetic Laboratory of Development and Diseases, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, People's Republic of China.
Liu
Bing
B
Yao
Huiyu
H
Li
Fangfei
F
Weng
Tujun
T
Yang
Guan
G
Li
Wenlong
W
Cheng
Xuan
X
Mao
Ning
N
Yang
Xiao
X
D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities / Q000473:pathology / Q000502:physiology*; D018031:Connexin 43 / Q000378:metabolism; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic; D009928:Organ Specificity; D020286:Pericytes / Q000473:pathology; D010920:Placenta / Q000473:pathology; D011247:Pregnancy; D042787:Receptor, TIE-2 / Q000378:metabolism; D051901:Smad4 Protein / Q000172:deficiency / Q000378:metabolism*
D042702:Angiopoietin-2; D018031:Connexin 43; D051901:Smad4 Protein; D042787:Receptor, TIE-2; C045073:Cre recombinase; D019426:Integrases