Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis
Wei Li, Qingle Li, Yang Jiao, Lingfeng Qin, Rahmat Ali, Jing Zhou, Jacopo Ferruzzi, Richard W. Kim, Arnar Geirsson, Harry C. Dietz, Stefan Offermanns, Jay D. Humphrey, George Tellides
Wei Li, Qingle Li, Yang Jiao, Lingfeng Qin, Rahmat Ali, Jing Zhou, Jacopo Ferruzzi, Richard W. Kim, Arnar Geirsson, Harry C. Dietz, Stefan Offermanns, Jay D. Humphrey, George Tellides
View: Text | PDF
Research Article Cardiology

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

Abstract

TGF-β is essential for vascular development; however, excess TGF-β signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-β overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF-β signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-β type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor–independent effects of TGF-β and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-β signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression.

Authors

Wei Li, Qingle Li, Yang Jiao, Lingfeng Qin, Rahmat Ali, Jing Zhou, Jacopo Ferruzzi, Richard W. Kim, Arnar Geirsson, Harry C. Dietz, Stefan Offermanns, Jay D. Humphrey, George Tellides

×

Figure 2

Tgfbr2 disruption in smooth muscle results in aortic thickening, dilatation, and dissection.

Options: View larger image (or click on image) Download as PowerPoint
Tgfbr2 disruption in smooth muscle results in aortic thickening, dilata...
(A) Gross appearance of ascending (Asc) and descending (Desc) thoracic aorta (arrows mark mural hematomas) in 8-week-old Myh11-CreERT2.Tgfbr2f/f mice treated with vehicle or tamoxifen for 5 days starting at 4 weeks of age. (B) Aortic dissection rates at various times after tamoxifen treatment of 4-week-old mice (0/28 after 0 weeks, 11/39 after 2 weeks, 19/40 after 4 weeks, 4/6 after 6 weeks, and 7/11 weeks after 26 weeks) or at 4 weeks after induction starting at different ages (10/13 at 3 weeks, 19/40 at 4 weeks, 3/16 at 6 weeks, 1/9 at 9 weeks, and 0/7 at 18 weeks). ***P < 0.001, χ2 test. (C) Aortic blood pressure of 6-week-old mice treated with vehicle or tamoxifen at 4 weeks of age; n = 6. *P < 0.05, t test. (D) Representative ultrasound images and ascending aorta diameters (blue lines) of 6-week-old mice treated with vehicle or tamoxifen at 4 weeks of age; n = 8. ***P < 0.001, t test. (E) H&E, EVG, and trichrome stains of the ascending aorta from 6- and 10-week-old mice treated with vehicle or tamoxifen at 4 weeks of age demonstrating progressive elastin fragmentation, elastic lamella widening, adventitial fibrosis, and mural thickening. Scale bars: 100 μm. (F) Medial and adventitial areas of ascending aortas with or without dissection (Dis) in 8-week-old mice treated with vehicle or tamoxifen at 4 weeks of age and (G) similar analysis of descending thoracic aortas; n = 3–12. **P < 0.01, ***P < 0.001, 1-way ANOVA.