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. 1998 Feb 15;101(4):731–736. doi: 10.1172/JCI1699

Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling.

R D Rudic 1, E G Shesely 1, N Maeda 1, O Smithies 1, S S Segal 1, W C Sessa 1
PMCID: PMC508619  PMID: 9466966

Abstract

The vascular endothelium mediates the ability of blood vessels to alter their architecture in response to hemodynamic changes; however, the specific endothelial-derived factors that are responsible for vascular remodeling are poorly understood. Here we show that endothelial-derived nitric oxide (NO) is a major endothelial-derived mediator controlling vascular remodeling. In response to external carotid artery ligation, mice with targeted disruption of the endothelial nitric oxide synthase gene (eNOS) did not remodel their ipsilateral common carotid arteries whereas wild-type mice did. Rather, the eNOS mutant mice displayed a paradoxical increase in wall thickness accompanied by a hyperplastic response of the arterial wall. These findings demonstrate a critical role for endogenous NO as a negative regulator of vascular smooth muscle proliferation in response to a remodeling stimulus. Furthermore, our data suggests that a primary defect in the NOS/NO pathway can promote abnormal remodeling and may facilitate pathological changes in vessel wall morphology associated with complex diseases such as hypertension and atherosclerosis.

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Selected References

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  1. Awolesi M. A., Sessa W. C., Sumpio B. E. Cyclic strain upregulates nitric oxide synthase in cultured bovine aortic endothelial cells. J Clin Invest. 1995 Sep;96(3):1449–1454. doi: 10.1172/JCI118181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Carmeliet P., Ferreira V., Breier G., Pollefeyt S., Kieckens L., Gertsenstein M., Fahrig M., Vandenhoeck A., Harpal K., Eberhardt C. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996 Apr 4;380(6573):435–439. doi: 10.1038/380435a0. [DOI] [PubMed] [Google Scholar]
  3. Carmeliet P., Moons L., Ploplis V., Plow E., Collen D. Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J Clin Invest. 1997 Jan 15;99(2):200–208. doi: 10.1172/JCI119148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cornwell T. L., Arnold E., Boerth N. J., Lincoln T. M. Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP. Am J Physiol. 1994 Nov;267(5 Pt 1):C1405–C1413. doi: 10.1152/ajpcell.1994.267.5.C1405. [DOI] [PubMed] [Google Scholar]
  5. Davies P. F. Flow-mediated endothelial mechanotransduction. Physiol Rev. 1995 Jul;75(3):519–560. doi: 10.1152/physrev.1995.75.3.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. García-Cardeña G., Oh P., Liu J., Schnitzer J. E., Sessa W. C. Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6448–6453. doi: 10.1073/pnas.93.13.6448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Garg U. C., Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989 May;83(5):1774–1777. doi: 10.1172/JCI114081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gibbons G. H., Dzau V. J. The emerging concept of vascular remodeling. N Engl J Med. 1994 May 19;330(20):1431–1438. doi: 10.1056/NEJM199405193302008. [DOI] [PubMed] [Google Scholar]
  9. Guyton J. R., Hartley C. J. Flow restriction of one carotid artery in juvenile rats inhibits growth of arterial diameter. Am J Physiol. 1985 Apr;248(4 Pt 2):H540–H546. doi: 10.1152/ajpheart.1985.248.4.H540. [DOI] [PubMed] [Google Scholar]
  10. Hansson G. K., Geng Y. J., Holm J., Hårdhammar P., Wennmalm A., Jennische E. Arterial smooth muscle cells express nitric oxide synthase in response to endothelial injury. J Exp Med. 1994 Aug 1;180(2):733–738. doi: 10.1084/jem.180.2.733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Iafrati M. D., Karas R. H., Aronovitz M., Kim S., Sullivan T. R., Jr, Lubahn D. B., O'Donnell T. F., Jr, Korach K. S., Mendelsohn M. E. Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nat Med. 1997 May;3(5):545–548. doi: 10.1038/nm0597-545. [DOI] [PubMed] [Google Scholar]
  12. Ignarro L. J., Buga G. M., Wood K. S., Byrns R. E., Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9265–9269. doi: 10.1073/pnas.84.24.9265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kamiya A., Togawa T. Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am J Physiol. 1980 Jul;239(1):H14–H21. doi: 10.1152/ajpheart.1980.239.1.H14. [DOI] [PubMed] [Google Scholar]
  14. Kohler T. R., Kirkman T. R., Kraiss L. W., Zierler B. K., Clowes A. W. Increased blood flow inhibits neointimal hyperplasia in endothelialized vascular grafts. Circ Res. 1991 Dec;69(6):1557–1565. doi: 10.1161/01.res.69.6.1557. [DOI] [PubMed] [Google Scholar]
  15. Kuchan M. J., Frangos J. A. Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells. Am J Physiol. 1994 Mar;266(3 Pt 1):C628–C636. doi: 10.1152/ajpcell.1994.266.3.C628. [DOI] [PubMed] [Google Scholar]
  16. Langille B. L., Bendeck M. P., Keeley F. W. Adaptations of carotid arteries of young and mature rabbits to reduced carotid blood flow. Am J Physiol. 1989 Apr;256(4 Pt 2):H931–H939. doi: 10.1152/ajpheart.1989.256.4.H931. [DOI] [PubMed] [Google Scholar]
  17. Langille B. L., O'Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science. 1986 Jan 24;231(4736):405–407. doi: 10.1126/science.3941904. [DOI] [PubMed] [Google Scholar]
  18. López-Farré A., Sánchez de Miguel L., Caramelo C., Gómez-Macías J., Garcia R., Mosquera J. R., de Frutos T., Millás I., Rivas F., Echezarreta G. Role of nitric oxide in autocrine control of growth and apoptosis of endothelial cells. Am J Physiol. 1997 Feb;272(2 Pt 2):H760–H768. doi: 10.1152/ajpheart.1997.272.2.H760. [DOI] [PubMed] [Google Scholar]
  19. Miyashiro J. K., Poppa V., Berk B. C. Flow-induced vascular remodeling in the rat carotid artery diminishes with age. Circ Res. 1997 Sep;81(3):311–319. doi: 10.1161/01.res.81.3.311. [DOI] [PubMed] [Google Scholar]
  20. Mondy J. S., Lindner V., Miyashiro J. K., Berk B. C., Dean R. H., Geary R. L. Platelet-derived growth factor ligand and receptor expression in response to altered blood flow in vivo. Circ Res. 1997 Sep;81(3):320–327. doi: 10.1161/01.res.81.3.320. [DOI] [PubMed] [Google Scholar]
  21. Murrell G. A., Jang D., Williams R. J. Nitric oxide activates metalloprotease enzymes in articular cartilage. Biochem Biophys Res Commun. 1995 Jan 5;206(1):15–21. doi: 10.1006/bbrc.1995.1003. [DOI] [PubMed] [Google Scholar]
  22. Noiri E., Hu Y., Bahou W. F., Keese C. R., Giaever I., Goligorsky M. S. Permissive role of nitric oxide in endothelin-induced migration of endothelial cells. J Biol Chem. 1997 Jan 17;272(3):1747–1752. doi: 10.1074/jbc.272.3.1747. [DOI] [PubMed] [Google Scholar]
  23. Numaguchi K., Egashira K., Takemoto M., Kadokami T., Shimokawa H., Sueishi K., Takeshita A. Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats. Hypertension. 1995 Dec;26(6 Pt 1):957–962. doi: 10.1161/01.hyp.26.6.957. [DOI] [PubMed] [Google Scholar]
  24. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  25. Papapetropoulos A., Desai K. M., Rudic R. D., Mayer B., Zhang R., Ruiz-Torres M. P., García-Cardeña G., Madri J. A., Sessa W. C. Nitric oxide synthase inhibitors attenuate transforming-growth-factor-beta 1-stimulated capillary organization in vitro. Am J Pathol. 1997 May;150(5):1835–1844. [PMC free article] [PubMed] [Google Scholar]
  26. Rubanyi G. M., Romero J. C., Vanhoutte P. M. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol. 1986 Jun;250(6 Pt 2):H1145–H1149. doi: 10.1152/ajpheart.1986.250.6.H1145. [DOI] [PubMed] [Google Scholar]
  27. Sarkar R., Meinberg E. G., Stanley J. C., Gordon D., Webb R. C. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res. 1996 Feb;78(2):225–230. doi: 10.1161/01.res.78.2.225. [DOI] [PubMed] [Google Scholar]
  28. Segal S. S., Kurjiaka D. T., Caston A. L. Endurance training increases arterial wall thickness in rats. J Appl Physiol (1985) 1993 Feb;74(2):722–726. doi: 10.1152/jappl.1993.74.2.722. [DOI] [PubMed] [Google Scholar]
  29. Sessa W. C., Pritchard K., Seyedi N., Wang J., Hintze T. H. Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression. Circ Res. 1994 Feb;74(2):349–353. doi: 10.1161/01.res.74.2.349. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Suri C., Jones P. F., Patan S., Bartunkova S., Maisonpierre P. C., Davis S., Sato T. N., Yancopoulos G. D. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996 Dec 27;87(7):1171–1180. doi: 10.1016/s0092-8674(00)81813-9. [DOI] [PubMed] [Google Scholar]
  32. Trachtman H., Futterweit S., Garg P., Reddy K., Singhal P. C. Nitric oxide stimulates the activity of a 72-kDa neutral matrix metalloproteinase in cultured rat mesangial cells. Biochem Biophys Res Commun. 1996 Jan 26;218(3):704–708. doi: 10.1006/bbrc.1996.0125. [DOI] [PubMed] [Google Scholar]
  33. Tronc F., Wassef M., Esposito B., Henrion D., Glagov S., Tedgui A. Role of NO in flow-induced remodeling of the rabbit common carotid artery. Arterioscler Thromb Vasc Biol. 1996 Oct;16(10):1256–1262. doi: 10.1161/01.atv.16.10.1256. [DOI] [PubMed] [Google Scholar]
  34. Tzeng E., Shears L. L., 2nd, Robbins P. D., Pitt B. R., Geller D. A., Watkins S. C., Simmons R. L., Billiar T. R. Vascular gene transfer of the human inducible nitric oxide synthase: characterization of activity and effects on myointimal hyperplasia. Mol Med. 1996 Mar;2(2):211–225. [PMC free article] [PubMed] [Google Scholar]
  35. Uematsu M., Ohara Y., Navas J. P., Nishida K., Murphy T. J., Alexander R. W., Nerem R. M., Harrison D. G. Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am J Physiol. 1995 Dec;269(6 Pt 1):C1371–C1378. doi: 10.1152/ajpcell.1995.269.6.C1371. [DOI] [PubMed] [Google Scholar]
  36. Yan Z. Q., Yokota T., Zhang W., Hansson G. K. Expression of inducible nitric oxide synthase inhibits platelet adhesion and restores blood flow in the injured artery. Circ Res. 1996 Jul;79(1):38–44. doi: 10.1161/01.res.79.1.38. [DOI] [PubMed] [Google Scholar]
  37. Ziche M., Morbidelli L., Masini E., Amerini S., Granger H. J., Maggi C. A., Geppetti P., Ledda F. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest. 1994 Nov;94(5):2036–2044. doi: 10.1172/JCI117557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. von der Leyen H. E., Gibbons G. H., Morishita R., Lewis N. P., Zhang L., Nakajima M., Kaneda Y., Cooke J. P., Dzau V. J. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1137–1141. doi: 10.1073/pnas.92.4.1137. [DOI] [PMC free article] [PubMed] [Google Scholar]

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