Sustained pulmonary hypertension and right ventricular hypertrophy after chronic hypoxia in mice with congenital deficiency of nitric oxide synthase 3 (original) (raw)

Abstract

Chronic hypoxia induces pulmonary hypertension and right ventricular (RV) hypertrophy. Nitric oxide (NO) has been proposed to modulate the pulmonary vascular response to hypoxia. We investigated the effects of congenital deficiency of endothelial NO synthase (NOS3) on the pulmonary vascular responses to breathing 11% oxygen for 3-6 wk. After 3 wk of hypoxia, RV systolic pressure was greater in NOS3-deficient than in wild-type mice (35+/-2 vs 28+/-1 mmHg, x+/-SE, P < 0.001). Pulmonary artery pressure (PPA) and incremental total pulmonary vascular resistance (RPI) were greater in NOS3-deficient than in wild-type mice (PPA 22+/-1 vs 19+/-1 mmHg, P < 0.05 and RPI 92+/-11 vs 55+/-5 mmHg.min.gram.ml-1, P < 0.05). Morphometry revealed that the proportion of muscularized small pulmonary vessels was almost fourfold greater in NOS3-deficient mice than in wild-type mice. After 6 wk of hypoxia, the increase of RV free wall thickness, measured by transesophageal echocardiography, and of RV weight/body weight ratio were more marked in NOS3-deficient mice than in wild-type mice (RV wall thickness 0.67+/-0.05 vs 0.48+/-0.02 mm, P < 0.01 and RV weight/body weight ratio 2.1+/-0.2 vs 1.6+/-0.1 mg. gram-1, P < 0.05). RV hypertrophy produced by chronic hypoxia was prevented by breathing 20 parts per million NO in both genotypes of mice. These results suggest that congenital NOS3 deficiency enhances hypoxic pulmonary vascular remodeling and hypertension, and RV hypertrophy, and that NO production by NOS3 is vital to counterbalance pulmonary vasoconstriction caused by chronic hypoxic stress.

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Selected References

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  1. Adnot S., Raffestin B., Eddahibi S., Braquet P., Chabrier P. E. Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia. J Clin Invest. 1991 Jan;87(1):155–162. doi: 10.1172/JCI114965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barer G. R., Bee D., Wach R. A. Contribution of polycythaemia to pulmonary hypertension in simulated high altitude in rats. J Physiol. 1983 Mar;336:27–38. doi: 10.1113/jphysiol.1983.sp014563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Biernacki W., Flenley D. C., Muir A. L., MacNee W. Pulmonary hypertension and right ventricular function in patients with COPD. Chest. 1988 Dec;94(6):1169–1175. doi: 10.1378/chest.94.6.1169. [DOI] [PubMed] [Google Scholar]
  4. Brent B. N., Berger H. J., Matthay R. A., Mahler D., Pytlik L., Zaret B. L. Physiologic correlates of right ventricular ejection fraction in chronic obstructive pulmonary disease: a combined radionuclide and hemodynamic study. Am J Cardiol. 1982 Aug;50(2):255–262. doi: 10.1016/0002-9149(82)90174-6. [DOI] [PubMed] [Google Scholar]
  5. Carville C., Raffestin B., Eddahibi S., Blouquit Y., Adnot S. Loss of endothelium-dependent relaxation in proximal pulmonary arteries from rats exposed to chronic hypoxia: effects of in vivo and in vitro supplementation with L-arginine. J Cardiovasc Pharmacol. 1993 Dec;22(6):889–896. doi: 10.1097/00005344-199312000-00018. [DOI] [PubMed] [Google Scholar]
  6. Crawley D. E., Zhao L., Giembycz M. A., Liu S., Barnes P. J., Winter R. J., Evans T. W. Chronic hypoxia impairs soluble guanylyl cyclase-mediated pulmonary arterial relaxation in the rat. Am J Physiol. 1992 Sep;263(3 Pt 1):L325–L332. doi: 10.1152/ajplung.1992.263.3.L325. [DOI] [PubMed] [Google Scholar]
  7. Dinh-Xuan A. T., Higenbottam T. W., Clelland C. A., Pepke-Zaba J., Cremona G., Butt A. Y., Large S. R., Wells F. C., Wallwork J. Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med. 1991 May 30;324(22):1539–1547. doi: 10.1056/NEJM199105303242203. [DOI] [PubMed] [Google Scholar]
  8. Frostell C. G., Blomqvist H., Hedenstierna G., Lundberg J., Zapol W. M. Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation. Anesthesiology. 1993 Mar;78(3):427–435. doi: 10.1097/00000542-199303000-00005. [DOI] [PubMed] [Google Scholar]
  9. Frostell C., Fratacci M. D., Wain J. C., Jones R., Zapol W. M. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation. 1991 Jun;83(6):2038–2047. doi: 10.1161/01.cir.83.6.2038. [DOI] [PubMed] [Google Scholar]
  10. Giaid A., Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995 Jul 27;333(4):214–221. doi: 10.1056/NEJM199507273330403. [DOI] [PubMed] [Google Scholar]
  11. Gruetter C. A., Gruetter D. Y., Lyon J. E., Kadowitz P. J., Ignarro L. J. Relationship between cyclic guanosine 3':5'-monophosphate formation and relaxation of coronary arterial smooth muscle by glyceryl trinitrate, nitroprusside, nitrite and nitric oxide: effects of methylene blue and methemoglobin. J Pharmacol Exp Ther. 1981 Oct;219(1):181–186. [PubMed] [Google Scholar]
  12. Hampl V., Archer S. L., Nelson D. P., Weir E. K. Chronic EDRF inhibition and hypoxia: effects on pulmonary circulation and systemic blood pressure. J Appl Physiol (1985) 1993 Oct;75(4):1748–1757. doi: 10.1152/jappl.1993.75.4.1748. [DOI] [PubMed] [Google Scholar]
  13. Hassid A., Arabshahi H., Bourcier T., Dhaunsi G. S., Matthews C. Nitric oxide selectively amplifies FGF-2-induced mitogenesis in primary rat aortic smooth muscle cells. Am J Physiol. 1994 Sep;267(3 Pt 2):H1040–H1048. doi: 10.1152/ajpheart.1994.267.3.H1040. [DOI] [PubMed] [Google Scholar]
  14. Huang P. L., Huang Z., Mashimo H., Bloch K. D., Moskowitz M. A., Bevan J. A., Fishman M. C. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995 Sep 21;377(6546):239–242. doi: 10.1038/377239a0. [DOI] [PubMed] [Google Scholar]
  15. Kouyoumdjian C., Adnot S., Levame M., Eddahibi S., Bousbaa H., Raffestin B. Continuous inhalation of nitric oxide protects against development of pulmonary hypertension in chronically hypoxic rats. J Clin Invest. 1994 Aug;94(2):578–584. doi: 10.1172/JCI117372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Roberts J. D., Jr, Roberts C. T., Jones R. C., Zapol W. M., Bloch K. D. Continuous nitric oxide inhalation reduces pulmonary arterial structural changes, right ventricular hypertrophy, and growth retardation in the hypoxic newborn rat. Circ Res. 1995 Feb;76(2):215–222. doi: 10.1161/01.res.76.2.215. [DOI] [PubMed] [Google Scholar]
  17. Roos C. M., Frank D. U., Xue C., Johns R. A., Rich G. F. Chronic inhaled nitric oxide: effects on pulmonary vascular endothelial function and pathology in rats. J Appl Physiol (1985) 1996 Jan;80(1):252–260. doi: 10.1152/jappl.1996.80.1.252. [DOI] [PubMed] [Google Scholar]
  18. Rossaint R., Falke K. J., López F., Slama K., Pison U., Zapol W. M. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med. 1993 Feb 11;328(6):399–405. doi: 10.1056/NEJM199302113280605. [DOI] [PubMed] [Google Scholar]
  19. Shaul P. W., North A. J., Brannon T. S., Ujiie K., Wells L. B., Nisen P. A., Lowenstein C. J., Snyder S. H., Star R. A. Prolonged in vivo hypoxia enhances nitric oxide synthase type I and type III gene expression in adult rat lung. Am J Respir Cell Mol Biol. 1995 Aug;13(2):167–174. doi: 10.1165/ajrcmb.13.2.7542896. [DOI] [PubMed] [Google Scholar]
  20. Shaul P. W., Wells L. B., Horning K. M. Acute and prolonged hypoxia attenuate endothelial nitric oxide production in rat pulmonary arteries by different mechanisms. J Cardiovasc Pharmacol. 1993 Dec;22(6):819–827. doi: 10.1097/00005344-199312000-00007. [DOI] [PubMed] [Google Scholar]
  21. Shesely E. G., Maeda N., Kim H. S., Desai K. M., Krege J. H., Laubach V. E., Sherman P. A., Sessa W. C., Smithies O. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13176–13181. doi: 10.1073/pnas.93.23.13176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Sprague R. S., Ellsworth M. L., Stephenson A. H., Lonigro A. J. ATP: the red blood cell link to NO and local control of the pulmonary circulation. Am J Physiol. 1996 Dec;271(6 Pt 2):H2717–H2722. doi: 10.1152/ajpheart.1996.271.6.H2717. [DOI] [PubMed] [Google Scholar]
  23. Steudel W., Ichinose F., Huang P. L., Hurford W. E., Jones R. C., Bevan J. A., Fishman M. C., Zapol W. M. Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene. Circ Res. 1997 Jul;81(1):34–41. doi: 10.1161/01.res.81.1.34. [DOI] [PubMed] [Google Scholar]
  24. Takahashi M., Ishida T., Traub O., Corson M. A., Berk B. C. Mechanotransduction in endothelial cells: temporal signaling events in response to shear stress. J Vasc Res. 1997 May-Jun;34(3):212–219. doi: 10.1159/000159225. [DOI] [PubMed] [Google Scholar]
  25. Uncles D. R., Daugherty M. O., Frank D. U., Roos C. M., Rich G. F. Nitric oxide modulation of pulmonary vascular resistance is red blood cell dependent in isolated rat lungs. Anesth Analg. 1996 Dec;83(6):1212–1217. doi: 10.1097/00000539-199612000-00014. [DOI] [PubMed] [Google Scholar]
  26. Xue C., Johns R. A. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995 Dec 14;333(24):1642–1644. doi: 10.1056/NEJM199512143332416. [DOI] [PubMed] [Google Scholar]
  27. Xue C., Johns R. A. Upregulation of nitric oxide synthase correlates temporally with onset of pulmonary vascular remodeling in the hypoxic rat. Hypertension. 1996 Nov;28(5):743–753. doi: 10.1161/01.hyp.28.5.743. [DOI] [PubMed] [Google Scholar]
  28. Xue C., Rengasamy A., Le Cras T. D., Koberna P. A., Dailey G. C., Johns R. A. Distribution of NOS in normoxic vs. hypoxic rat lung: upregulation of NOS by chronic hypoxia. Am J Physiol. 1994 Dec;267(6 Pt 1):L667–L678. doi: 10.1152/ajplung.1994.267.6.L667. [DOI] [PubMed] [Google Scholar]
  29. Yoshioka K., Fisher J. W. Nitric oxide enhancement of erythropoietin production in the isolated perfused rat kidney. Am J Physiol. 1995 Oct;269(4 Pt 1):C917–C922. doi: 10.1152/ajpcell.1995.269.4.C917. [DOI] [PubMed] [Google Scholar]
  30. Zapol W. M., Jones R. Vascular components of ARDS. Clinical pulmonary hemodynamics and morphology. Am Rev Respir Dis. 1987 Aug;136(2):471–474. doi: 10.1164/ajrccm/136.2.471. [DOI] [PubMed] [Google Scholar]
  31. Zapol W. M., Kobayashi K., Snider M. T., Greene R., Laver M. B. Vascular obstruction causes pulmonary hypertension in severe acute respiratory failure. Chest. 1977 Feb;71(2 Suppl):306–307. doi: 10.1378/chest.71.2_supplement.306. [DOI] [PubMed] [Google Scholar]