Rebuttal from Drs. Rabinovitch, Chesler, and Moulthen
Three issues raised in the article by McLoughlin and McMurtryclaiming "no loss of arteries" in hypoxia have been addressedin our original previous article: 1) loss of arteries has alwaysreferred to precapillary arteries rather than veins or capillaries,2) restoration of pressure to normal values can occur in theface of a remodeled vascular bed with fewer vessels, witnessminimal elevation in mean pulmonary artery pressures even afterpneumonectomy, and 3) there may be rodent strains in which lossof arteries may not be a feature of hypoxia-induced vascularremodeling. Among the papers cited to support the authors' contentionthat loss of precapillary arteries following chronic hypoxiacannot be, are only two utilizing comprehensive morphometricanalysis, but these evaluated Wistar (2, 3) not Sprague-Dawleyrats. So it is possible that Wistar rats do not show this featurein hypoxia. The reference by Kay et al. (5) reported failureto show loss of arteries either in response to chronic hypoxiaor following monocrotaline injection, but only by measuringvessels of a certain diameter range, and, therefore, would haveincluded veins. Now there is ample evidence from many groupsthat supports loss of precapillary arteries in monocrotaline-inducedpulmonary hypertension as shown in studies by Zhao et al. (10)using fluorescent microsphere. References by Meyrick and Reid(6) and Hislop and Reid (4) do document a loss of barium-filledarteries in chronic hypoxia. The reference by Mooi and Wagenvoort(7a) only questions arterial loss, but without evidence. Thereis no evidence of failure to find loss of vessels in the referenceby Brusselmans (1) and, in fact, the Carmeliet group has reportedloss of distal pulmonary arteries in hypoxia in another publicationas cited. As the authors point out, the number of groups reportingloss of vessels in rodents following exposure to hypoxia outweighthose groups that fail to observe this abnormality. Additionalstudies are cited claiming that in younger animals the lossof arteries may not consider a change in alveolar number, butprevious studies have incorporated morphometric analyses oftotal alveolar number and still find a chronic hypoxia inducedloss of precapillary arteries in developing lungs (8). Finallywe provide evidence to show specifically that "quantitativemodels of the rat pulmonary arterial tree morphometry appliedto hypoxia-induced arterial remodeling" show a significant decreasein pulmonary arterial distensibility in the rat (7, 9).
REFERENCES
Brusselmans K, Compernolle V, Tjwa M, Wiesener MS, Maxwell PH, Collen D, Carmeliet P. Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Invest 111: 1519–1527, 2003.[CrossRef][ISI][Medline]
Emery CJ, Bee D, Barer GR. Mechanical properties and reactivity of vessels in isolated perfused lungs of chronically hypoxic rats. Clin Sci (Lond) 61: 569–580, 1981.[Medline]
Finlay M, Barer GR, Suggett AJ. Quantitative changes in the rat pulmonary vasculature in chronic hypoxia–relation to haemodynamic changes. Q J Exp Physiol 71: 151–163, 1986.[Abstract/Free Full Text]
Hislop A, Reid L. New findings in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. Br J Exp Pathol 57: 542–554, 1976.[ISI][Medline]
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.[Abstract]
Meyrick B, Reid L. Hypoxia and incorporation of 3H-thymidine by cells of the rat pulmonary arteries and alveolar wall. Am J Pathol 96: 51–70, 1979.[Abstract]
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.[Abstract/Free Full Text]
Mooi W, Wagenvoort CA. Decreased numbers of pulmonary blood vessels: reality or artifact? J Pathol 141: 441–447, 1983.[CrossRef][ISI][Medline]
Rabinovitch M, Gamble WJ, Miettinen OS, Reid L. Age and sex influence on pulmonary hypertension of chronic hypoxia on recovery. Am J Physiol Heart Circ Physiol 240: H62–H72, 1981.[Abstract/Free Full Text]
Tozzi CA, Christiansen DL, Poiani GJ, Riley DJ. Excess collagen in hypertensive pulmonary arteries decreases vascular distensibility. Am J Respir Crit Care Med 149: 1317–1326, 1994.[Abstract]
Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy inestablished disease. Circ Res 96: 442–450, 2005.[Abstract/Free Full Text]
