Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-β

Papke, Christina L.; Cao, Jianjun; Kwartler, Callie S.; Villamizar, Carlos; Byanova, Katerina L.; Lim, Soram; Sreenivasappa, Harini; Fischer, Grant M.; Pham, John; Rees, Meredith L.; Wang, Miranda; Chaponnier, Christine; Gabbiani, Giulio; Khakoo, Aarif Y.; Chandra, Joya; Trache, Andreea; Zimmer, Warren E.; Milewicz, Dianna M.

doi:10.1093/hmg/ddt167

Cited by 41 publications

(54 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, a gain in proliferative function may be a cause as well as a consequence of SMC dedifferentiation. Similarly to recent findings by the Milewicz group in Myh11-mutant and Acta2-deficient mice (29,30), we hypothesize that altered SMC mechanosensing may link the contractile dysfunction, MAPK activation, and medial hyperplasia that occur after Tgfbr2 disruption (Figure 7).…”

Section: Discussionsupporting

confidence: 86%

“…Contractile dysfunction is thought to underlie aortic aneurysm and dissection due to MYH11 and ACTA2 mutations in humans (25), and dedifferentiation of aortic SMCs harboring TGFBR2 missense mutations from clinical specimens has been described (10). In mice, Myh11 mutation and Acta2 deletion cause a milder phenotype characterized by abnormalities in vascular contractility without overt aortic disease; additional vascular injury in these strains unmasks a gain in proliferative function of SMCs (29,30). Although contractile protein expression gradually and modestly declines in our Tgfbr2 KO aortas, the early and robust loss of MLC phosphorylation correlates better with the rapid onset of vascular disease following TβRII inactivation.…”

Section: Discussionmentioning

confidence: 99%

“…We searched for additional pathogenetic effects of TβRII inactivation, since genetic disruption of contractile molecule expression or activity in mice does not result in overt aortic dissection or aneurysm phenotypes (28)(29)(30). We assessed for excessive SMC proliferation, as TGF-β has well-described growth regulatory effects (1) and medial hyperplasia is associated with certain aortic diseases (31)(32)(33).…”

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Reduction in proliferation was associated with increased expression of SM α-actin. Whereas these observations were incidental to the characterization of immortalized cells, they are consistent with results showing greater proliferation by primary smooth muscle cells and fibroblasts from patients heterozygous for other ACTA2 mutations, as well as from Acta2 −/− mice (16,30). In vivo, vascular smooth muscle hyperplasia in response to carotid artery injury greatly exceeded wild-type in Acta2 −/− mice (30).…”

Section: Discussionsupporting

confidence: 82%

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Liu

Chang

Grinnell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) α-actin encoded by ACTA2. We focus here on ACTA2-R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM α-actin-R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells. Primary dermal fibroblasts from R258C patients exhibited increased proliferative capacity compared with controls, consistent with inhibition of growth suppression attributed to SM α-actin. Telomeraseimmortalized lines of control and R258C human dermal fibroblasts were established and SM α-actin expression induced with adenovirus encoding myocardin-related transcription factor A, a potent coactivator of ACTA2. Two-dimensional Western blotting confirmed induction of both wild-type and mutant SM α-actin in heterozygous ACTA2-R258C cells. Expression of mutant SM α-actin in heterozygous ACTA2-R258C fibroblasts abrogated the significant effects of SM α-actin induction on formation of stress fibers and focal adhesions, filamentous to soluble actin ratio, matrix contraction, and cell migration. These results demonstrate that R258C dominantly disrupts cytoskeletal functions attributed to SM α-actin in fibroblasts and are consistent with deficiencies in multiple cytoskeletal functions. Thus, cellular defects due to this ACTA2 mutation in both aortic smooth muscle cells and adventitial fibroblasts may contribute to development of TAAD and proliferative occlusive vascular disease.thoracic aortic aneurysms | ACTA2 mutation | vascular disease | cell migration | human fibroblasts

show abstract

“…In PNAS, Lu et al (3) addresses two of these mutations, primarily R258C and secondarily R258H, to try to gain insight into how changes induced by these mutations lead to TAAD by affecting actin function. Vascular material from an affected individual carrying the R258C mutation shows that the muscle layer of the vessel wall is abnormal, with disorganized structure and a dearth of contractile filaments compared with normal smooth muscle, suggesting abnormal filament assembly, protein instability, or failure of the assembled cytoskeleton to withstand the forces imposed on it by myosin during contraction of the muscle (4,5). However, the advanced disease stage at the time of tissue resection prevents early stages of the disease from being addressed.…”

mentioning

confidence: 99%