Circulation Research. 2005
Published online before print June 16, 2005, doi: 10.1161/01.RES.0000174287.17953.83
Published online before print June 16, 2005, doi: 10.1161/01.RES.0000174287.17953.83
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on December 16, 2004
Revised on June 6, 2005
Accepted on June 8, 2005
Inhibition of Rho-Kinase Attenuates Hypoxia-Induced Angiogenesis in the Pulmonary Circulation
Jean-Marc Hyvelin ;
From the Departments of Physiology (J.-M.H., K.H., A.N., R.J.P., P.M.) and Pharmacology (C.M.C.), Conway Institute of Biomolecular and Biomedical Research and the Dublin Molecular Medicine Centre (P.M.), University College, Dublin, Ireland.
* To whom correspondence should be addressed. E-mail: paul.mcloughlin{at}ucd.ie.
Pulmonary hypertension (PH) is a common complication of chronic hypoxic lung diseases, which increase morbidity and mortality. Hypoxic PH has previously been attributed to structural changes in the pulmonary vasculature including narrowing of the vascular lumen and loss of vessels, which produce a fixed increase in resistance. Using quantitative stereology, we now show that chronic hypoxia caused PH and remodeling of the blood vessel walls in rats but that this remodeling did not lead to structural narrowing of the vascular lumen. Sustained inhibition of the RhoA/Rho-kinase pathway throughout the period of hypoxic exposure attenuated PH and prevented remodeling in intra-acinar vessels without enlarging the structurally determined lumen diameter. In chronically hypoxic lungs, acute Rho kinase inhibition markedly decreased PVR but did not alter the alveolar to arterial oxygen gap. In addition to increased vascular resistance, chronic hypoxia induced Rho kinase-dependent capillary angiogenesis. Thus, hypoxic PH was not caused by fixed structural changes in the vasculature but by sustained vasoconstriction, which was largely Rho kinase dependent. Importantly, this vasoconstriction had no role in ventilation-perfusion matching and optimization of gas exchange. Rho kinase also mediated hypoxia-induced capillary angiogenesis, a previously unrecognized but potentially important adaptive response.
Key words: pulmonary hypertension • angiogenesis • RhoA • Rho-kinase • Y-27632
Related Article:
- Vascular Remodeling Versus Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension: A Time for Reappraisal?
- Kurt R. Stenmark and Ivan F. McMurtry
Circ. Res. 2005 97: 95-98.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  H. N. Woodward, A. Anwar, S. Riddle, L. Taraseviciene-Stewart, M. Fragoso, K. R. Stenmark, and E. V. Gerasimovskaya PI3K, Rho, and ROCK play a key role in hypoxia-induced ATP release and ATP-stimulated angiogenic responses in pulmonary artery vasa vasorum endothelial cells Am J Physiol Lung Cell Mol Physiol, November 1, 2009; 297(5): L954 - L964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Howell, C. M. Costello, M. Sands, I. Dooley, and P. McLoughlin L-Arginine promotes angiogenesis in the chronically hypoxic lung: a novel mechanism ameliorating pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, June 1, 2009; 296(6): L1042 - L1050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. O. Leonard, K. Howell, S. F. Madden, C. M. Costello, D. G. Higgins, C. T. Taylor, and P. McLoughlin Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung Am. J. Respir. Crit. Care Med., November 1, 2008; 178(9): 977 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Gao, A. D. Portugal, J. Liu, S. Negash, W. Zhou, J. Tian, R. Xiang, L. D. Longo, and J. U. Raj Preservation of cGMP-induced relaxation of pulmonary veins of fetal lambs exposed to chronic high altitude hypoxia: role of PKG and Rho kinase Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L889 - L896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gien, G. J. Seedorf, V. Balasubramaniam, N. Tseng, N. Markham, and S. H. Abman Chronic intrauterine pulmonary hypertension increases endothelial cell Rho kinase activity and impairs angiogenesis in vitro Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L680 - L687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Lammers, P. H. Kao, H. J. Qi, K. Hunter, C. Lanning, J. Albietz, S. Hofmeister, R. Mecham, K. R. Stenmark, and R. Shandas Changes in the structure-function relationship of elastin and its impact on the proximal pulmonary arterial mechanics of hypertensive calves Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1451 - H1459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. L. Jernigan, B. R. Walker, and T. C. Resta Reactive oxygen species mediate RhoA/Rho kinase-induced Ca2+ sensitization in pulmonary vascular smooth muscle following chronic hypoxia Am J Physiol Lung Cell Mol Physiol, September 1, 2008; 295(3): L515 - L529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Costello, K. Howell, E. Cahill, J. McBryan, M. Konigshoff, O. Eickelberg, S. Gaine, F. Martin, and P. McLoughlin Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L272 - L284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Homma, T. Nagaoka, V. Karoor, M. Imamura, L. Taraseviciene-Stewart, L. A. Walker, K. A. Fagan, I. F. McMurtry, and M. Oka Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L71 - L78. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B Wojciak-Stothard New drug targets for pulmonary hypertension: Rho GTPases in pulmonary vascular remodelling Postgrad. Med. J., July 1, 2008; 84(993): 348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bhattacharya Lung neovascularization: a tale of two circulations Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L417 - L418. [Full Text] [PDF]
|
|
|
|
 |
|
 D. O. Schwenke, J. T. Pearson, K. Kangawa, K. Umetani, and M. Shirai Changes in macrovessel pulmonary blood flow distribution following chronic hypoxia: assessed using synchrotron radiation microangiography J Appl Physiol, January 1, 2008; 104(1): 88 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Dhaliwal, D. B. Casey, A. J. Greco, A. M. Badejo Jr., T. B. Gallen, S. N. Murthy, B. D. Nossaman, A. L. Hyman, and P. J. Kadowitz Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in L-NAME-treated rats Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1306 - L1313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. McLoughlin and I. McMurtry Counterpoint: Chronic Hypoxia-induced Pulmonary Hypertension does not Lead to Loss of Pulmonary Vasculature J Appl Physiol, October 1, 2007; 103(4): 1451 - 1453. [Full Text] [PDF]
|
|
|
|
|
|
Rebuttal from Drs. Mcloughlin and Mcmurtry J Appl Physiol, October 1, 2007; 103(4): 1453 - 1454. [Full Text] [PDF]
|
|
|
|
|
|
M. Rabinovitch, N. Chesler, and R. C. Molthen Point:Counterpoint: Chronic hypoxia-induced pulmonary hypertension does/does not lead to loss of pulmonary vasculature J Appl Physiol, October 1, 2007; 103(4): 1449 - 1451. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Oka, V. Karoor, N. Homma, T. Nagaoka, E. Sakao, S. M. Golembeski, J. Limbird, M. Imamura, S. A. Gebb, K. A. Fagan, et al. Dehydroepiandrosterone upregulates soluble guanylate cyclase and inhibits hypoxic pulmonary hypertension Cardiovasc Res, June 1, 2007; 74(3): 377 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. P. Robertson Point: Release of an endothelium-derived vasoconstrictor and RhoA/Rho kinase-mediated calcium sensitization of smooth muscle cell contraction are/are not the main effectors for full and sustained hypoxic pulmonary vasoconstriction J Appl Physiol, May 1, 2007; 102(5): 2071 - 2072. [Full Text] [PDF]
|
|
|
|
|
|
R. E. Girgis, S. Mozammel, H. C. Champion, D. Li, X. Peng, L. Shimoda, R. M. Tuder, R. A. Johns, and P. M. Hassoun Regression of chronic hypoxic pulmonary hypertension by simvastatin Am J Physiol Lung Cell Mol Physiol, May 1, 2007; 292(5): L1105 - L1110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Crossno Jr., C. V. Garat, J. E. B. Reusch, K. G. Morris, E. C. Dempsey, I. F. McMurtry, K. R. Stenmark, and D. J. Klemm Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L885 - L897. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Oka, N. Homma, L. Taraseviciene-Stewart, K. G. Morris, D. Kraskauskas, N. Burns, N. F. Voelkel, and I. F. McMurtry Rho Kinase-Mediated Vasoconstriction Is Important in Severe Occlusive Pulmonary Arterial Hypertension in Rats Circ. Res., March 30, 2007; 100(6): 923 - 929. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Gao, A. D. Portugal, S. Negash, W. Zhou, L. D. Longo, and J. Usha Raj Role of Rho kinases in PKG-mediated relaxation of pulmonary arteries of fetal lambs exposed to chronic high altitude hypoxia Am J Physiol Lung Cell Mol Physiol, March 1, 2007; 292(3): L678 - L684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Stenmark, K. A. Fagan, and M. G. Frid Hypoxia-Induced Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms Circ. Res., September 29, 2006; 99(7): 675 - 691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Davie, E. V. Gerasimovskaya, S. E. Hofmeister, A. P. Richman, P. L. Jones, J. T. Reeves, and K. R. Stenmark Pulmonary Artery Adventitial Fibroblasts Cooperate with Vasa Vasorum Endothelial Cells to Regulate Vasa Vasorum Neovascularization: A Process Mediated by Hypoxia and Endothelin-1 Am. J. Pathol., June 1, 2006; 168(6): 1793 - 1807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nagaoka, S. A. Gebb, V. Karoor, N. Homma, K. G. Morris, I. F. McMurtry, and M. Oka Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat J Appl Physiol, March 1, 2006; 100(3): 996 - 1002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Noma, N. Oyama, and J. K. Liao Physiological role of ROCKs in the cardiovascular system Am J Physiol Cell Physiol, March 1, 2006; 290(3): C661 - C668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Stenmark and I. F. McMurtry Vascular Remodeling Versus Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension: A Time for Reappraisal? Circ. Res., July 22, 2005; 97(2): 95 - 98. [Full Text] [PDF]
|
|