Overexpression of transforming growth factor β1 in arterial endothelium causes hyperplasia, apoptosis, and cartilaginous metaplasia

Schulick, Andrew H.; Taylor, Allen J.; Zuo, Wenbao; Qiu, Chen; Dong, Gang; Woodward, R.; Agah, Ramtin; Roberts, Anita B.; Virmani, Renu; Dichek, David A.

doi:10.1073/pnas.95.12.6983

Cited by 173 publications

(138 citation statements)

References 40 publications

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“…In the heart, Sox9 is required for proper organization the valvular ECM proteins (60), whereas in the gonads, Sox9 regulates many ECM proteins as well as modifiers of the ECM such as matrix metalloproteinases (61,62). Sox9 also plays a role in fibrotic and sclerotic disorders in various tissues, in which Sox9 causes excessive and inappropriate ECM deposition by activating ECM proteins (63)(64)(65)(66)(67)(68). Furthermore, Sox9 plays a critical role during chondrogenesis (30), and ChiP analysis in chondrocytes has shown that Sox9 directly binds to loci of 18 different ECM genes, including Col2a1 (69).…”

Section: Discussionmentioning

confidence: 99%

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

Rockich¹,

Hrycaj

Shih

et al. 2013

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

248

261

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Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in the adult lung. Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are critical to ensuring branching morphogenesis occurs properly. Here, we describe a role for the transcription factor Sox9 during lung branching morphogenesis. Sox9 is expressed at the distal tips of the branching epithelium in a highly dynamic manner as branching occurs and is down-regulated starting at embryonic day 16.5, concurrent with the onset of terminal differentiation of type 1 and type 2 alveolar cells. Using epithelial-specific genetic loss-and gain-of-function approaches, our results demonstrate that Sox9 controls multiple aspects of lung branching. Fine regulation of Sox9 levels is required to balance proliferation and differentiation of epithelial tip progenitor cells, and loss of Sox9 leads to direct and indirect cellular defects including extracellular matrix defects, cytoskeletal disorganization, and aberrant epithelial movement. Our evidence shows that unlike other endoderm-derived epithelial tissues, such as the intestine, Wnt/β-catenin signaling does not regulate Sox9 expression in the lung. We conclude that Sox9 collectively promotes proper branching morphogenesis by controlling the balance between proliferation and differentiation and regulating the extracellular matrix.organogenesis | campomelic dysplasia

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Section: Discussionmentioning

confidence: 99%

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

Rockich¹,

Hrycaj

Shih

et al. 2013

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

248

261

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“…In this context, it is worth noting that direct transfer of TGF-␤ 1 gene into arteries results in fibrocellular hyperplasia (33) and that this multifunctional cytokine also can induce vascular smooth muscle cell hypertrophy (34). Transdifferentiation of vascular smooth muscle cells into chondrocytes and intimal growth also have been observed after transfection of the TGF-␤ 1 gene into murine arteries (35). Differential sensitivity of vascular cells to TGF-␤ 1 signaling also might be relevant because TGF-␤ 1 is reported to potentiate platelet-derived growth factor (PDGF)-induced proliferation of vascular smooth muscle cells of the spontaneously hypertensive rat but not the vascular smooth muscle cells of the normotensive Wistar-Kyoto rat (36).…”

Section: How Might Tgf-␤1 Contribute To the Pathogenesis Of Hypertensmentioning

confidence: 99%

Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: A novel mediator of hypertension and/or target organ damage

Suthanthiran

Li²,

Song³

et al. 2000

Proceedings of the National Academy of Sciences

192

126

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Hypertension, a remediable risk factor for stroke, cardiovascular disease, and renal failure, affects 50 million individuals in the United States alone. African Americans (blacks) have a higher incidence and prevalence of hypertension and hypertension-associated target organ damage compared with Caucasian Americans (whites). Herein, we explored the hypotheses that transforming growth factor-␤1 (TGF-␤1) is hyperexpressed in hypertensives compared with normotensives and that TGF-␤1 overexpression is more frequent in blacks compared with whites. These hypotheses were stimulated by our recent demonstration that TGF-␤1 is hyperexpressed in blacks with end-stage renal disease compared with white end-stage renal disease patients and by the biological attributes of TGF-␤1, which include induction of endothelin-1 expression, stimulation of renin release, and promotion of vascular and renal disease when TGF-␤ 1 is produced in excess. TGF-␤1 profiles were determined in black and white hypertensive subjects and normotensive controls and included circulating protein concentrations, mRNA steady-state levels, and codon 10 genotype. Our investigation demonstrated that TGF-␤1 protein levels are highest in black hypertensives, and TGF-␤1 protein as well as TGF-␤1 mRNA levels are higher in hypertensives compared with normotensives. The proline allele at codon 10 (Pro 10 ) was more frequent in blacks compared with whites, and its presence was associated with higher levels of TGF-␤1 mRNA and protein. Our findings support the idea that TGF-␤ 1 hyperexpression is a risk factor for hypertension and hypertensive complications and provides a mechanism for the excess burden of hypertension in blacks.

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“…TGF-b signaling affects both vascular differentiation and proliferation, and overexpression of the TGF-b1 ligand promotes intimal growth and apoptosis simultaneously in vascular endothelium. 32 The pleiotropic nature of TGF-b as a growth factor offers a potential explanation for the variable complications of hereditary hemorrhagic telangiectasia. The net effect of dysfunction of activin-receptor-like kinase 1 may depend on local vascular interactions and other environmental or genetic factors.…”

Section: Known Features Of Phmentioning

confidence: 99%