HIF2A Gain-of-Function Mutation Modulates the Stiffness of Smooth Muscle Cells and Compromises Vascular Mechanics

2020 ◽  
Author(s):  
Xin Chan ◽  
Joon Eoh ◽  
Eugenia Volkova ◽  
Rebecca Black ◽  
Lilly Fang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Vascular Mechanics ◽  
Gain Of Function

scholarly journals HIF2A Gain-of-function Mutation Modulates the Stiffness of Smooth Muscle Cells and Compromises Vascular Mechanics

iScience ◽  
2021 ◽  
pp. 102246
Author(s):  
Xin Yi Chan ◽  
Eugenia Volkova ◽  
Joon Eoh ◽  
Rebecca Black ◽  
Lilly Fang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Vascular Mechanics ◽  
Gain Of Function

Abstract 4275: TGFBR2 Mutations Reduce Expression of Contractile Proteins in Aortic Smooth Muscle Cells and Predispose Individuals to Thoracic Aortic Aneurysms and Dissections

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Sakiko Inamoto ◽  
Callie Kwartler ◽  
Andrea Lafont ◽  
Yao Yun Liang ◽  
Van Tran Fadulu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Matched Control ◽  
Muscle Cells ◽  
Contractile Proteins ◽  
Aortic Aneurysms ◽  
Gain Of Function ◽  
Age And Gender ◽  
Thoracic Aortic Aneurysms ◽  
And Gender

Mutations in the TGF-β receptor type II gene ( TGFBR2 ) cause thoracic aortic aneurysms and dissections (TAAD). Studies have suggested a gain of function effect for these mutations, leading to increased TGF-β signaling in the aortic media and resulting in vascular disease. We sought to characterize the phenotype of smooth muscle cells (SMCs) harboring heterozygous missense TGFBR2 mutations and our data suggest that instead of a gain of function, TGFBR2 mutations cause TAAD as a result of a loss of function resulting in defective SMC differentiation. Using primary aortic SMCs from patients harboring TGFBR2 mutations (n=4), we show a global decrease in expression of SMC contractile proteins ( ACTA2 , MYH11 , CNN1 , SMTN , TPM1 , TPM2 , p <0.001) by quantitative PCR analysis when these cells are compared with age and gender matched control SMCs (n=4), along with no change in the expression of cytoskeletal proteins. Consistent with the decreased expression of contractile proteins in the mutant cells, there was increased expression of S100A4, a marker of de-differentiated SMCs (p<0.001). Analysis of fixed and frozen aortas from patients with TGFBR2 mutations (n=3) confirmed decreased in vivo expression of SMC contractile proteins when compared to control aortas (n=3). In control SMCs, addition of TGF- β significantly increased the expression of the SMC contractile proteins but the TGFBR2 SMCs showed no significant increase in expression of these proteins with TGF-β stimulation. We found that fibroblasts explanted from patients with TGFBR2 mutations (n=8) consistently fail to transform into myofibroblasts as assessed by expression of SMC contractile proteins after TGF-β stimulation, when compared with age and gender matched control fibroblasts (n=8). Finally, introduction of TGFBR2 missense mutations into a mouse mesenchymal embryonic cell line that is used as a model of SMC differentiation (10T1/2 cells) disrupts the expression of contractile proteins in these cells when assessed post-differentiation. These data suggest that TGFBR2 mutations disrupt differentiation of SMCs and myofibroblasts. This is the first genetic defect identified to lead to defective SMC differentiation.

Immunogold localization of HMB-45 antigen in pulmonary lymphangiomyomatosis

1995 ◽  
Vol 53 ◽  
pp. 998-999
Author(s):  
J.M. Minda ◽  
E. Dessy ◽  
G. G. Pietra
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Room Temperature ◽  
Osmium Tetroxide ◽  
Muscle Cells ◽  
Ultrastructural Localization ◽  
Reproductive Age ◽  
Thin Sections ◽  
Smooth Muscle Proliferation ◽  
Hmb 45

Pulmonary lymphangiomyomatosis (PLAM) is a rare disease occurring exclusively in women of reproductive age. It involves the lungs, lymph nodes and lymphatic ducts. In the lungs, it is characterized by the proliferation of smooth muscle cells around lymphatics in the bronchovascular bundles, lobular septa and pleura The nature of smooth muscle proliferation in PLAM is still unclear. Recently, reactivity of the smooth muscle cells for HMB-45, a melanoma-related antigen has been reported by immunohistochemistry. The purpose of this study was the ultrastructural localization of HMB-45 immunoreactivity in these cells using gold-labeled antibodies.Lung tissue from three cases of PLAM, referred to our Institution for lung transplantation, was embedded in either Poly/Bed 812 post-fixed in 1% osmium tetroxide, or in LR White, without osmication. For the immunogold technique, thin sections were placed on Nickel grids and incubated with affinity purified, monoclonal anti-melanoma antibody HMB-45 (1:1) (Enzo Diag. Co) overnight at 4°C. After extensive washing with PBS, grids were treated with Goat-anti-mouse-IgG-Gold (5nm) (1:10) (Amersham Life Sci) for 1 hour, at room temperature.

173: Lipid Rafts are Negative Regulators of TGFβ Signaling in Ureteral Smooth Muscle Cells

2004 ◽  
Vol 171 (4S) ◽  
pp. 46-46
Author(s):  
Carlos R. Estrada ◽  
Theodora Danciu ◽  
Maximilian Stehr ◽  
Joseph Khoury ◽  
Keith R. Solomon ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Lipid Rafts ◽  
Muscle Cells ◽  
Negative Regulators ◽  
Tgfβ Signaling
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