Conditional inactivation of TGF-β type II receptor in smooth muscle cells and epicardium causes lethal aortic and cardiac defects

Abstract

To understand the role of TGF-β signaling in cardiovascular development, we generated mice with conditional deletion of the TGF-β type II receptor (TβRII) gene (Tgfbr2) in cells expressing the smooth muscle cell-specific protein SM22α. The SM22α promoter was active in tissues involved in cardiovascular development: vascular smooth muscle cells (VSMCs), epicardium and myocardium. All SM22-Cre(+/-)/Tgfbr2 (flox/flox) embryos died during the last third of gestation. About half the mutant embryos exhibited heart defects (ventricular myocardium hypoplasia and septal defects). All mutant embryos displayed profound vascular abnormalities in the descending thoracic aorta (irregular outline and thickness, occasional aneurysms and elastic fiber disarray). Restriction of these defects to the descending thoracic aorta occurred despite similar levels of Tgfbr2 invalidation in the other portions of the aorta, the ductus arteriosus and the pulmonary trunk. Immunocytochemistry identified impairment of VSMC differentiation in the coronary vessels and the descending thoracic aorta as crucial for the defects. Ventricular myocardial hypoplasia, when present, was associated to impaired α-SMA differentiation of the epicardium-derived coronary VSMCs. Tgfbr2 deletion in the VSMCs of the descending thoracic aorta diminished the number of α-SMA-positive VSMC progenitors in the media at E11.5 and drastically decreased tropoelastin (from E11.5) and fibulin-5 (from E.12.5) synthesis and/or deposition. Defective elastogenesis observed in all mutant embryos and the resulting dilatation and probable rupture of the descending thoracic aorta might explain the late embryonic lethality. To conclude, during mouse development, TGF-β plays an irreplaceable role on the differentiation of the VSMCs in the coronary vessels and the descending thoracic aorta.

Renal afferent arteriolar and tubuloglomerular feedback reactivity in mice with conditional deletions of adenosine 1 receptors

“…1A, A1AR mRNA levels in whole kidney tissue of SmCre/ A1ARff mice were reduced to about half in the cre-positive animals, whereas the expression of A2 receptors was not significantly affected. An even more pronounced reduction of A1AR expression was observed in the heart, consistent with the wide SM22 alpha expression in both vascular and myocardial cells during early cardiac development (15,17). The presence of cre recombinase did not detectably affect A1AR expression in the brain.…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…Prenatal or perinatal ablation of TGF-b signaling in mouse models by deletion of Tgfbr2 in VSMCs with a VSMC-specific Cre (Langlois et al 2010), neural crest-and mesoderm-specific Cre (Choudhary et al 2009), or an inducible VSMC-specific Cre (Li et al 2014) results in defective elastogenesis, vessel wall dilation, aneurysm, and dissection. However, deletion of Tgfbr2 in VSMCs after 8 weeks of age has no apparent consequence on VSMC function and vessel wall homeostasis (Li et al 2014), suggesting that complete loss of TGF-b signaling in adult VSMCs does not cause major pathology in the adult vessel wall.…”

DiGeorge Syndrome Critical Region 8 (DGCR8) Protein-mediated microRNA Biogenesis Is Essential for Vascular Smooth Muscle Cell Development in Mice

“…Mortality-The SM22-Cre transgenic mouse line has been widely used to delete target genes in VSMCs because of the restricted expression of Cre recombinase in VSMCs of the aorta, cerebral vessels, bladder, intestine, and uterus (12)(13)(14)(15). To determine the role of DGCR8 in VSMCs, we generated DGCR8 cKO mice by crossing DGCR8 loxp/loxp mice with SM22-Cre transgenic mice.…”