Author + information
- Received February 6, 2009
- Accepted April 15, 2009
- Published online June 30, 2009.
- Nicholas W. Morrell, MA, MD⁎,⁎ (, )
- Serge Adnot, MD, PhD†,
- Stephen L. Archer, MD‡,
- Jocelyn Dupuis, MD, PhD§,
- Peter Lloyd Jones, PhD∥,
- Margaret R. MacLean, PhD¶,
- Ivan F. McMurtry, PhD#,
- Kurt R. Stenmark, MD⁎⁎,
- Patricia A. Thistlethwaite, MD, PhD††,
- Norbert Weissmann, PhD‡‡,
- Jason X.-J. Yuan, MD, PhD§§ and
- E. Kenneth Weir, MD∥∥
- ↵⁎Reprint requests and correspondence:
Dr. Nicholas W. Morrell, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom
Pulmonary arterial hypertension (PAH) is caused by functional and structural changes in the pulmonary vasculature, leading to increased pulmonary vascular resistance. The process of pulmonary vascular remodeling is accompanied by endothelial dysfunction, activation of fibroblasts and smooth muscle cells, crosstalk between cells within the vascular wall, and recruitment of circulating progenitor cells. Recent findings have reestablished the role of chronic vasoconstriction in the remodeling process. Although the pathology of PAH in the lung is well known, this article is concerned with the cellular and molecular processes involved. In particular, we focus on the role of the Rho family guanosine triphosphatases in endothelial function and vasoconstriction. The crosstalk between endothelium and vascular smooth muscle is explored in the context of mutations in the bone morphogenetic protein type II receptor, alterations in angiopoietin-1/TIE2 signaling, and the serotonin pathway. We also review the role of voltage-gated K+channels and transient receptor potential channels in the regulation of cytosolic [Ca2+] and [K+], vasoconstriction, proliferation, and cell survival. We highlight the importance of the extracellular matrix as an active regulator of cell behavior and phenotype and evaluate the contribution of the glycoprotein tenascin-c as a key mediator of smooth muscle cell growth and survival. Finally, we discuss the origins of a cell type critical to the process of pulmonary vascular remodeling, the myofibroblast, and review the evidence supporting a contribution for the involvement of endothelial-mesenchymal transition and recruitment of circulating mesenchymal progenitor cells.
Please see the end of this article for each author's conflict of interest information.
- Received February 6, 2009.
- Accepted April 15, 2009.
- American College of Cardiology Foundation
- Endothelial Dysfunction in PAH
- The SMC in PAH
- Crosstalk Between Vascular Cells
- Cellular and Molecular Consequences of BMPR-II Mutation
- The Extracellular Matrix
- Origins of the Myofibroblast in PAH
- Circulating Mesenchymal Progenitor Cells in Pulmonary Vascular Remodeling
- Author Disclosures