Inactivation of Smad5 in endothelial cells and smooth muscle cells demonstrates that Smad5 is required for cardiac homeostasis.
Smads are intracellular signaling proteins that transduce signals elicited by members of the transforming growth factor (TGF)-beta superfamily. Smad5 and Smad1 are highly homologous, and they mediate primarily bone morphogenetic protein (Bmp) signals. We used the Cre-loxP system and Sm22-Cre and Tie-1-Cre mice to study the function of Smad5 in the developing blood vessel wall. Analysis of embryos demonstrated that deletion of Smad5 in endothelial or smooth muscle cells resulted in a normal organization of embryonic and extra-embryonic vasculature. Angiogenic assays performed in adult mice revealed that mutant mice display a comparable angiogenic and vascular remodeling response to control mice. In Sm22-Cre; Smad5(fl/-) mice, Smad5 is also deleted in cardiomyocytes. Echocardiographic analysis on those 9-month-old female mice demonstrated larger left ventricle internal diameters and decreased fractional shortening compared with control littermates without signs of cardiac hypertrophy. The decreased cardiac contractility was associated with a decreased performance in a treadmill experiment. In isolated cardiomyocytes, fractional shortening was significantly reduced compared with control cells. These data demonstrate that restricted deletion of Smad5 in the blood vessel wall results in viable mice. However, loss of Smad5 in cardiomyocytes leads to a mild heart defect.
Umans
Lieve
L
Department for Molecular and Developmental Genetics, VIB, Leuven, Belgium.
Cox
Luk
L
Tjwa
Marc
M
Bito
Virginie
V
Vermeire
Liesbeth
L
Laperre
Kjell
K
Sipido
Karin
K
Moons
Lieve
L
Huylebroeck
Danny
D
Zwijsen
An
A
D000818:Animals; D000831:Animals, Newborn; D001808:Blood Vessels / Q000254:growth & development / Q000378:metabolism; D004452:Echocardiography; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000254:growth & development* / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D016133:Polymerase Chain Reaction; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism*
D051902:Smad5 Protein; C497798:Smad5 protein, mouse