The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension
Abstract
Mutations in the bone morphogenetic protein type II receptor gene ( BMPR2 ) are the major genetic cause of familial pulmonary arterial hypertension (FPAH). Although smooth muscle cell proliferation contributes to the vascular remodeling observed in PAH, the role of BMPs in this process and the impact of BMPR2 mutation remains unclear. Studies involving normal human pulmonary artery smooth muscle cells (PASMCs) suggest site-specific responses to BMPs. Thus, BMP-4 inhibited proliferation of PASMCs isolated from proximal pulmonary arteries, but stimulated proliferation of PASMCs from peripheral arteries, and conferred protection from apoptosis. These differences were not caused by differential activation of BMP signaling pathways because exogenous BMP-4 led to phosphorylation of Smad1, p38 MAPK , and ERK1/2 in both cell types. However, the proproliferative effect of BMP-4 on peripheral PASMCs was found to be p38 MAPK /ERK-dependent. Conversely, overexpression of dominant-negative Smad1 converted the response to BMP-4 in proximal PASMCs from inhibitory to proliferative. Furthermore, we confirmed that proximal PASMCs harboring kinase domain mutations in BMPR2 are deficient in Smad signaling and are unresponsive to the growth suppressive effect of BMP-4. Moreover, we show that the pulmonary vasculature of patients with familial and idiopathic PAH are deficient in the activated form of Smad1. We conclude that defective Smad signaling and unopposed p38 MAPK /ERK signaling, as a consequence of mutation in BMPR2 , underlie the abnormal vascular cell proliferation observed in familial PAH.
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Cited by
Cellular and Molecular Basis of Pulmonary Arterial Hypertension
Morrell, N. W., Adnot, S., Archer, S. L., Dupuis, J., Lloyd Jones, P., MacLean, M. R., McMurtry, I. F., Stenmark, K. R., Thistlethwaite, P. A., Weissmann, N., et al. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.04.018 · Cited by 819
Self-citationMechanisms of disease: pulmonary arterial hypertension
Schermuly, R. T., Ghofrani, H. A., Wilkins, M. R., & Grimminger, F. (2011) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2011.87 · Cited by 800
Interleukin-6 Overexpression Induces Pulmonary Hypertension
Steiner, M. K., Syrkina, O. L., Kolliputi, N., Mark, E. J., Hales, C. A., & Waxman, A. B. (2009) · Circulation Research · doi:10.1161/circresaha.108.182014 · Cited by 655
Sotatercept for the Treatment of Pulmonary Arterial Hypertension
Humbert, M., McLaughlin, V., Gibbs, J. S. R., Gomberg-Maitland, M., Hoeper, M. M., Preston, I. R., Souza, R., Waxman, A., Escribano Subias, P., Feldman, J., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2024277 · Cited by 608
Smooth muscle cell-driven vascular diseases and molecular mechanisms of VSMC plasticity
Frismantiene, A., Philippova, M., Erne, P., & Resink, T. J. (2018) · Cellular Signalling · doi:10.1016/j.cellsig.2018.08.019 · Cited by 406
Metadata
- Authors
- Yang, X., Long, L., Southwood, M., Rudarakanchana, N., Upton, P. D., Jeffery, T. K., Atkinson, C., Chen, H., Trembath, R. C., & Morrell, N. W.
- Venue
- Circulation Research
- Published
- 2005-05-27
- Volume
- 96
- Issue
- 10
- Pages
- 1053-1063
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2083998789
- Cited by
- 364
- References
- 28
- FWCI
- 17.02
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension. https://app.cochat.ai/papers/10.1161/01.res.0000166926.54293.68
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- Yang, X., Long, L., Southwood, M., Rudarakanchana, N., Upton, P. D., Jeffery, T. K., Atkinson, C., Chen, H., Trembath, R. C., & Morrell, N. W. (2005). Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension. Circulation Research. https://doi.org/10.1161/01.res.0000166926.54293.68
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