Rebuttal from Drs. Mcloughlin and Mcmurtry

Abstract

POINT-COUNTERPOINTRebuttal from Drs. Mcloughlin and McmurtryPublished Online:01 Oct 2007https://doi.org/10.1152/japplphysiol.00274.2007cMoreSectionsPDF (44 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat We read with great interest the arguments put forward by Drs. Rabinovitch, Chesler, and Molthen to support their case (8). They raise a number of important issues that warrant further investigation. However, not surprisingly, we cannot agree with all that they propose. We discuss here those issues not dealt with in our original submission.Regarding the limitations of the barium-gelatin infusion technique, our opponents argue that studies in which small pulmonary arteries were identified using anti-PECAM immunostaining also report vascular loss. However, others who have used anti-von Willebrand Factor or elastin staining to identify vessels did not detect reduced vascular density in hypoxic hypertensive lungs (2, 4, 5).Dr. Rabinovitch and her coauthors next discuss studies of the pulmonary vasculature undertaken using contrast (PFOB)-based microCT imaging. While this elegant approach holds much promise for the future, we do not believe it can at present address the issue of angiogenesis or rarefaction in the lung. First, the resolution of the technique means that the smallest vessel that can be visualized is at best 70 μm in diameter (6). Second, the principal pathway analysis that this technique uses does not examine parallel distal pathways. Finally, as we have all agreed, full relaxation of vascular tone is essential for angiographic techniques to accurately detect structural changes. It seems unlikely that brief exposure to papaverine, which was used to prepare the lungs for the PFOB-microCT studies (6), could have achieved this. Rho kinase inhibitors appear to be uniquely potent in reducing vascular tone in the chronically hypoxic pulmonary circulation (3, 7), and to our knowledge transient exposure to papaverine has not been shown to be similarly effective. Thus the PFOB-microCT technique cannot provide unambiguous information regarding distal vessel number.We agree with Dr. Rabinovitch and her colleagues that Rho kinase inhibitors have only been shown to abolish chronic hypoxic pulmonary hypertension at low flow rates and their effects should be examined over a larger range of flows. They suggest that angiogenesis and precapillary arteriolar loss may occur simultaneously. Such a mechanism could reconcile seemingly disparate views on this issue and warrants further investigation. Finally, we agree that there can be major discrepancies between hemodynamic changes and structural changes in the vascular bed following chronic hypoxia. Factors such as reduced vascular compliance may contribute importantly to right ventricular overloading, although it should be recognized that, in addition to changes in structure, smooth muscle contraction can also alter compliance (1).REFERENCES1 Bank AJ, Kaiser DR. Smooth muscle relaxation: effects on arterial compliance, distensibility, elastic modulus, and pulse wave velocity. Hypertension 32: 356–359, 1998.Crossref | PubMed | ISI | Google Scholar2 Brusselmans K, Compernolle V, Tjwa M, Wiesener MS, Maxwell PH, Collen D, Carmeliet P. Heterozygous deficiency of hypoxia-induciblefactor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Invest 111: 1519–1527, 2003.Crossref | PubMed | ISI | Google Scholar3 Hyvelin JM, Howell K, Nichol A, Costello CM, Preston RJ, McLoughlin P. Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation. Circ Res 97: 185–191, 2005.Crossref | PubMed | ISI | Google Scholar4 Kay JM, Suyama KL, Keane PM. Failure to show decrease in small pulmonary blood vessels in rats with experimental pulmonary hypertension. Thorax 37: 927–930, 1982.Crossref | PubMed | ISI | Google Scholar5 Pascaud MA, Griscelli F, Raoul W, Marcos E, Opolon P, Raffestin B, Perricaudet M, Adnot S, Eddahibi S. Lung overexpression of angiostatin aggravates pulmonary hypertension in chronically hypoxic mice. Am J Respir Cell Mol Biol 29: 449–457, 2003.Crossref | PubMed | ISI | Google Scholar6 Molthen RC, Karau KL, Dawson CA. Quantitative models of the rat pulmonary arterial tree morphometry applied to hypoxia-induced arterial remodeling. J Appl Physiol 97: 2372–2384, 2004.Link | ISI | Google Scholar7 Nagaoka T, Morio Y, Casanova N, Bauer N, Gebb S, McMurtry I, Oka M. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 287: L665–L672, 2004.Link | ISI | Google Scholar8 Rabinovitch M, Chesler N, Molthen C. Point: Chronic hypoxia-induced pulmonary hypertension does lead to loss of pulmonary vasculature. J Appl Physiol; doi:10.1152/japplphysiol.00274.2007.Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 103Issue 4October 2007Pages 1453-1454 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00274.2007cHistory Published online 1 October 2007 Published in print 1 October 2007 Metrics