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Nitric Oxide in Endothelial Dysfunction and Vascular Remodeling: Clinical Correlates and Experimental Links

1999; Elsevier BV; Volume: 64; Issue: 3 Linguagem: Inglês

10.1086/302304

1537-6605

R. Daniel Rudic, William C. Sessa,

Cardiac Ischemia and Reperfusion

The patency of the vascular system is essential to maintain normal tissue function. Fortunately for us, the genetic program of vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) endows them with the capacity to respond to physiological and pathophysiological stimuli and to rearrange their architecture to maintain adequate blood flow according to the metabolic demand of the tissue. Rapid calibration of lumen diameter can occur through vasomotor control governed by the sympathetic nervous sytem and vasoactive factors. Long-term structural adaptation, perhaps reflecting the summation of many short-term vasomotor events, occurs through a process called "vascular remodeling." Vascular remodeling is the ability of the vessel wall to reorganize its cellular and extracellular components in response to a chronic stimulus (Gibbons and Dzau Gibbons and Dzau, 1994Gibbons GH Dzau VJ The emerging concept of vascular remodeling.N Engl J Med. 1994; 330: 1431-1438Crossref PubMed Scopus (1288) Google Scholar). Experimental studies have shown that increases in blood flow due to an arteriovenous shunt will increase vessel diameter; conversely, reductions in blood flow will reduce vascular diameter. On the basis of these findings, it is believed that chronic reduction in blood flow initiates a signaling cascade that leads blood vessels to contract acutely and remodel themselves, creating a smaller vascular lumen. This remodeling reduces the shear stress and the circumferential wall strain imposed by the lower flow rates (Kamiya and Togawa Kamiya and Togawa, 1980Kamiya A Togawa T Adaptive regulation of wall shear stress to flow change in the canine carotid artery.Am J Physiol. 1980; 239: H14-H21PubMed Google Scholar; Langille and O'Donnell Langille and O'Donnell, 1986Langille BL O'Donnell F Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent.Science. 1986; 231: 405-407Crossref PubMed Scopus (899) Google Scholar). The layered structure of the vascular system facilitates information transfer from the lumen of the vessel into the underlying smooth muscle and then to surrounding tissue. Likewise, the vessel responds to neural input and tissue factors to influence the smooth muscle and the endothelium. The position of the vascular endothelium at the interface of blood is ideally situated to serve as a tranducer, to relay hemodynamic and biochemical changes into molecular events in the smooth muscle layer (Davies Davies, 1995Davies PF Flow-mediated endothelial mechanotransduction.Physiol Rev. 1995; 75: 519-560Crossref PubMed Scopus (2220) Google Scholar). Smooth muscle cells in the medial layer respond to endothelial cell mediators and/or extracellular matrix (ECM) molecules, allowing expansion or retraction of smooth muscle mass. The outermost layer, the adventitia, consists mostly of fibroblasts and produces growth factors, ECM, and proteases/protease inhibitors that can regulate proliferation and migration of smooth muscle cells. Similar remodeling of the endothelium must also occur during normal angiogenesis, and there is ample evidence showing that increases or decreases in blood flow can influence capillary densities in the heart and skeletal muscle. This plasticity of blood vessel architecture is essential for macro- and microvascular remodeling. An increasing volume of evidence indicates that abnormal vascular remodeling contributes to such cardiovascular diseases as hypertension, atherosclerosis, transplant arteriosclerosis, and restenosis. In the past decade, many molecules essential for vasculogenesis, angiogenesis, and vessel structure have been identified that, when deleted, cause embryonic lethality due to vascular defects. Although these genes must play fundamental roles in vascular development or remodeling, we have little knowledge of the hierarchy of events underlying physiological or pathological remodeling in the mature vessel wall. We argue, in the present article, that signals transmitted bidirectionally across the endothelium direct the remodeling of blood vessel architecture in the adult. We hypothesize that the inability of the endothelium to couple hemodynamic events efficiently to the production of the gaseous second messenger, nitric oxide (NO), contributes to abnormal vascular remodeling in many diseases. Both human essential hypertension and animal models of this condition show enhanced peripheral vascular resistance due to impaired remodeling of resistance arterioles. The increase in resistance arises in part because of impaired structural adaptation to elevated blood pressure and in part because of excess vasoconstriction. In histologic analysis, this change is measured as an increase in the cross-sectional area of the media, relative to the area of the lumen of specialized "resistance" arterioles. The increase in media/lumen ratio can result from any of the following: (1) abnormal lumenal remodeling resulting in a narrower lumen, (2) an increase in muscle mass (wall thickness) with no change in lumen diameter, or (3) a decrease in external diameter of the vessel, leading to encroachment of the lumen (Heagerty et al. Heagerty et al., 1993Heagerty AM Aalkjaer C Bund SJ Korsgaard N Mulvany MJ Small artery structure in hypertension: dual processes of remodeling and growth.Hypertension. 1993; 21: 391-397Crossref PubMed Scopus (565) Google Scholar). Similarly, in human atherosclerosis there is ample evidence for active remodeling during the early stages of disease prior to significant lumenal stenosis. Compensatory enlargement occurs in peripheral vessels and in coronary arteries with lesions and represents an adaptive cellular response to preserve lumen area and blood flow. This "remodeled" vessel may revert to a more normal structure if the lesion regresses, but persistent or worsening lesions may provoke an abnormal remodeling response, thus contributing to occlusive disease, plaque rupture, and thrombosis (see Birnbaum et al. Birnbaum et al., 1997Birnbaum Y Fishbein MC Luo H Nishioka T Siegel RJ Regional remodeling of atherosclerotic arteries: a major determinant of clinical manifestations of disease.J Am Coll Cardiol. 1997; 30: 1149-1164Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar for a comprehensive review). Although the causes of these diseases are different, in both cases endothelial dysfunction occurs concomitantly with changes in vascular structure—that is, with vascular wall thickening in hypertension (Girerd et al. Girerd et al., 1994Girerd X Mourad JJ Copie X Moulin C Acar C Safar M Laurent S Noninvasive detection of an increased vascular mass in untreated hypertensive patients.Am J Hypertens. 1994; 7: 1076-1084PubMed Google Scholar; Ghiadoni et al. Ghiadoni et al., 1998Ghiadoni L Taddei S Virdis A Sudano I Di Legge V Meola M Di Venanzio L et al.Endothelial function and common carotid artery wall thickening in patients with essential hypertension.Hypertension. 1998; 32: 25-32Crossref PubMed Scopus (140) Google Scholar) and with compensatory vessel wall enlargement in atherosclerosis (Birnbaum et al. Birnbaum et al., 1997Birnbaum Y Fishbein MC Luo H Nishioka T Siegel RJ Regional remodeling of atherosclerotic arteries: a major determinant of clinical manifestations of disease.J Am Coll Cardiol. 1997; 30: 1149-1164Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Endothelial dysfunction, defined here as an impairment in endothelium-dependent relaxation of blood vessels (Harrison Harrison, 1997Harrison DG Cellular and molecular mechanisms of endothelial cell dysfunction.J Clin Invest. 1997; 100: 2153-2157Crossref PubMed Scopus (881) Google Scholar), is a reversible condition, as evidenced by the recent clinical trials with drugs such as angiotensin-converting enzyme inhibitors (Mancini et al. Mancini et al., 1996Mancini GB Henry GC Macaya C O'Neill BJ Pucillo AL Carere RG Wargovich TJ et al.Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction).Circulation. 1996; 94: 258-265Crossref PubMed Scopus (1039) Google Scholar) and cholesterol-lowering agents (Treasure et al. Treasure et al., 1995Treasure CB Klein JL Weintraub WS Talley JD Stillabower ME Kosinski AS Zhang J et al.Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease.N Engl J Med. 1995; 332: 481-487Crossref PubMed Scopus (1181) Google Scholar). These functional responses are largely mediated by the endogenous vasodilator NO, an unusual signaling molecule that has been identified as the endothelium-derived relaxing factor—as originally characterized by Furchgott and Zawadski in Furchgott and Zawadski, 1980Furchgott RF Zawadski JV The obligatory role of the endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature. 1980; 288: 373-376Crossref PubMed Scopus (9605) Google Scholar. Mutations in the gene for endothelial isoform of NO synthase (eNOS) seemed to provide an attractive explanation for these abnormal responses. However, linkage studies show little evidence that eNOS is a candidate gene in vascular disease. In patients with essential hypertension (Bonnardeaux et al. Bonnardeaux et al., 1995Bonnardeaux A Nadaud S Charru A Jeunemaitre X Corvol P Soubrier F Lack of evidence for linkage of the endothelial cell nitric oxide synthase gene to essential hypertension.Circulation. 1995; 91: 96-102Crossref PubMed Google Scholar; Hunt et al. Hunt et al., 1996Hunt SC Williams CS Sharma AM Inoue I Williams RR Lalouel JM Lack of linkage between the endothelial nitric oxide synthase gene and hypertension.J Hum Hypertens. 1996; 10: 27-30PubMed Google Scholar) and in genetic models of hypertension in rats (Deng and Rapp Deng and Rapp, 1997Deng AY Rapp JP Absence of linkage for "endothelial" nitric oxide synthase locus to blood pressure in Dahl rats.Hypertension. 1997; 29: 49-52Crossref PubMed Scopus (20) Google Scholar), polymorphisms of the eNOS gene (NOS3) do not segregate with high blood pressure. This lack of linkage occurs despite evidence that whole-body basal NO production in patients with essential hypertension is diminished (Wang et al. Wang et al., 1997Wang XL Mahaney MC Sim AS Wang J Blangero J Almasy L Badenhop RB et al.Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels.Arterioscler Thromb Vasc Biol. 1997; 17: 3147-3153Crossref PubMed Scopus (276) Google Scholar) and that offspring of hypertensive patients have endothelial dysfunction (Taddei et al. Taddei et al., 1996Taddei S Virdis A Mattei P Ghiadoni L Sudano I Salvetti A Defective l-arginine-nitric oxide pathway in offspring of essential hypertensive patients.Circulation. 1996; 94: 1298-1303Crossref PubMed Scopus (286) Google Scholar). A recent study in a Japanese population of patients with essential hypertension has shown that a missense variant of eNOS (Glu298Asp) is significantly associated with the disease; however, the functional relevance of this variant is not yet known (Miyamoto et al. Miyamoto et al., 1998Miyamoto Y Saito Y Kajiyama N Yoshimura M Shimasaki Y Nakayama M Kamitani S et al.Endothelial nitric oxide synthase gene is positively associated with essential hypertension.Hypertension. 1998; 32: 3-8Crossref PubMed Scopus (469) Google Scholar). This same mutation is associated with coronary vasospasm (Yoshimura et al. Yoshimura et al., 1998Yoshimura M Yasue H Nakayama M Shimasaki Y Sumida H Sugiyama S Kugiyama K et al.A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese.Hum Genet. 1998; 103: 65-69Crossref PubMed Scopus (355) Google Scholar) and myocardial infarction (Shimasaki et al. Shimasaki et al., 1998Shimasaki Y Yasue H Yoshimura M Nakayama M Kugiyama K Ogawa H Harada E et al.Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction.J Am Coll Cardiol. 1998; 31: 1506-1510Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar) in this population. A recent study in France (Lacolley et al. Lacolley et al., 1998Lacolley P Gautier S Poirier O Pannier B Cambien F Benetos A Nitric oxide synthase gene polymorphisms, blood pressure and aortic stiffness in normotensive and hypertensive subjects.J Hypertens. 1998; 16: 31-35Crossref PubMed Scopus (149) Google Scholar) showed a higher prevalence of the Glu298 Asp mutation in hypertensives compared with normotensive patients, but no association between this allele and blood pressure or aortic stiffness was noted. The only linkage study correlating mutations in the eNOS gene positively with endothelial dysfunction is a study showing a positive association between an intronic polymorphism and patients who were smokers or former smokers with a history of myocardial infarction (Wang et al. Wang et al., 1996Wang XL Sim AS Badenhop RF McCredie RM Wilcken DE A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene.Nat Med. 1996; 2: 41-45Crossref PubMed Scopus (532) Google Scholar). If abnormal function or expression of eNOS is involved in the disease processes associated with endothelial dysfunction, it is unlikely to be a primary determinant of disease in the populations studied thus far. A major breakthrough in understanding the importance of the endothelium in the remodeling process was the development of surgical models of flow-dependent remodeling. Thus, high-flow states, similar to those seen after long-term exercise training, can be studied by introducing an arterial anastomosis, or flow can be reduced in the common carotid artery by ligation of the external carotid. Using the latter model, which mimics critical stenosis, Langille and O'Donnell (Langille and O'Donnell, 1986Langille BL O'Donnell F Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent.Science. 1986; 231: 405-407Crossref PubMed Scopus (899) Google Scholar) elegantly demonstrated that the endothelium, or a substance produced by the endothelium, was essential for remodeling toward a smaller lumen after a long-term flow reduction. Results of this study suggested that the endothelium sensed the hemodynamic changes and initiated the reorganization of the preexisting cellular and extracellular components. This remodeling requires coordinated changes in cellular proliferation, apoptosis, migration, cell organization, and matrix-integrin interactions throughout the layered structure of the vessel. Because of the complexity of the process, it is not surprising that it can be perturbed by persistently elevated blood pressures, local inflammation, high cholesterol, or the deposition of oxidized lipids. Pharmacologic studies using inhibitors of NOS have implicated NO as an important endothelial mediator of flow- or pressure- induced arterial remodeling. Long-term treatment of rats with the NOS inhibitor, nitro-l-arginine methyl ester (l-NAME), causes a sustained increase in systemic blood pressure accompanied by marked microvascular remodeling, as judged by an increase in wall-to-lumen ratios of resistance coronary arteries (Numaguchi et al. Numaguchi et al., 1995Numaguchi 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; 26: 957-962Crossref PubMed Scopus (200) Google Scholar). Of interest, in this study, coadministration of hydralazine to offset the pressor effects of l-NAME did not affect the remodeling of coronary vessels, suggesting that the elevated pressure, per se, could not account for pathological remodeling. Indeed, NO is a potent vasodilator, but it may influence vascular remodeling because of its nonhemodynamic actions. This signaling molecule has profound effects on many cell types—inhibiting platelet and leukocyte adherence to the endothelium, promoting endothelial and preventing smooth muscle–cell migration and proliferation, influencing extracellular matrix synthesis and degradation, and regulating gene expression. In addition, NO acts as a second messenger for the actions of many growth factors, peptides, coagulation factors, and hormones. Luvara et al. (Luvara et al., 1998Luvara G Pueyo ME Philippe M Mandet C Savoie F Henrion D Michel JB Chronic blockade of NO synthase activity induces a proinflammatory phenotype in the arterial wall: prevention by angiotensin II antagonism.Arterioscler Thromb Vasc Biol. 1998; 18: 1408-1416Crossref PubMed Scopus (116) Google Scholar) showed that long-term blockade of whole-body NOS leads to a proinflammatory vascular phenotype associated with the up-regulation of cellular adhesion molecules ICAM-1 and VCAM-1 and inflammatory cell infiltration. In a study examining the importance of NO in high-flow remodeling of the carotid artery, rabbits with surgically created arteriovenous fistulas were given nonpressor doses of l-NAME (Tronc et al. Tronc et al., 1996Tronc 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; 16: 1256-1262Crossref PubMed Scopus (296) Google Scholar), and remodeling was examined. As predicted, l-NAME blocked the flow-induced increase in luminal remodeling, supporting the idea that activation of eNOS by changes in flow promotes NO release and the orchestration of events leading to remodeling. These results have been corroborated in rats (Guzman et al. Guzman et al., 1997Guzman RJ Abe K Zarins CK Flow-induced arterial enlargement is inhibited by suppression of nitric oxide synthase activity in vivo.Surgery. 1997; 122 (discussion 279-280): 273-279Abstract Full Text PDF PubMed Scopus (107) Google Scholar). Recent studies with eNOS knockout mice confirm that eNOS serves as a major regulator of physiological and pathological remodeling. eNOS knockout mice are viable, with slightly less than Mendelian segregation of the appropriate genotypes (Huang et al. Huang et al., 1995Huang PL Huang Z Mashimo H Bloch KD Moskowitz MA Bevan JA Fishman MC Hypertension in mice lacking the gene for endothelial nitric oxide synthase.Nature. 1995; 377: 239-242Crossref PubMed Scopus (1715) Google Scholar; Shesely et al. Shesely et al., 1996Shesely EG Maeda N Kim HS Desai KM Krege JH Laubach VE Sherman PA et al.Elevated blood pressures in mice lacking endothelial nitric oxide synthase.Proc Natl Acad Sci USA. 1996; 93: 13176-13181Crossref PubMed Scopus (764) Google Scholar; Godecke et al. Godecke et al., 1998Godecke A Decking UK Ding Z Hirchenhain J Bidmon HJ Godecke S Schrader J Coronary hemodynamics in endothelial NO synthase knockout mice.Circ Res. 1998; 82: 186-194Crossref PubMed Scopus (229) Google Scholar; Gregg et al. Gregg et al., 1998Gregg AR Schauer A Shi O Liu Z Lee CGL O'Brien WE Limb reduction defects in endothelial nitric oxide synthase-deficient mice.Am J Physiol. 1998; 275: H2319-H2324PubMed Google Scholar). The mice are moderately hypertensive, have resting bradycardia in vivo (Shesely et al. Shesely et al., 1996Shesely EG Maeda N Kim HS Desai KM Krege JH Laubach VE Sherman PA et al.Elevated blood pressures in mice lacking endothelial nitric oxide synthase.Proc Natl Acad Sci USA. 1996; 93: 13176-13181Crossref PubMed Scopus (764) Google Scholar; Godecke et al. Godecke et al., 1998Godecke A Decking UK Ding Z Hirchenhain J Bidmon HJ Godecke S Schrader J Coronary hemodynamics in endothelial NO synthase knockout mice.Circ Res. 1998; 82: 186-194Crossref PubMed Scopus (229) Google Scholar), and do not exhibit either pressor responses to l-NAME or endothelium-dependent relaxations in response to acetylcholine (Huang et al. Huang et al., 1995Huang PL Huang Z Mashimo H Bloch KD Moskowitz MA Bevan JA Fishman MC Hypertension in mice lacking the gene for endothelial nitric oxide synthase.Nature. 1995; 377: 239-242Crossref PubMed Scopus (1715) Google Scholar). One of four studies indicated a trend toward limb-reduction defects in eNOS knockout mice (Gregg et al. Gregg et al., 1998Gregg AR Schauer A Shi O Liu Z Lee CGL O'Brien WE Limb reduction defects in endothelial nitric oxide synthase-deficient mice.Am J Physiol. 1998; 275: H2319-H2324PubMed Google Scholar), but all studies confirm that there were no gross vascular phenotypes, showing that eNOS-derived NO is not an essential regulator of vasculogenesis, angiogenesis, or remodeling during embryogenesis. Rather, the vascular roles of NO manifest themselves in the adult mouse. Rudic et al. (Rudic et al., 1998Rudic RD Shesely EG Maeda N Smithies O Segal SS Sessa WC Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling.J Clin Invest. 1998; 101: 731-736Crossref PubMed Scopus (673) Google Scholar) recently developed a mouse model of physiological remodeling in which ligation of the left external carotid artery for 2 weeks provokes a reduction of lumen diameter and medial cell number of the ipsilateral common carotid artery. This reduction in lumen diameter was triggered by a 30% reduction in blood flow (R. D. Rudic and W. C. Sessa, unpublished data). Surprisingly, eNOS mutant mice were unable to reduce lumen diameter in response to external carotid artery ligation. Recent data (fig. 1) showed a gene-dosage effect of disruption of the eNOS locus on impaired luminal remodeling—that is, loss of one copy of the eNOS gene yields an intermediate phenotype between control and homozygote knockout mice. Equally provocative, the vascular media in abnormally remodeled vessels from eNOS knockout mice were hyperplastic, as shown by marked increases in wall thickness, medial nuclei, and bromodeoxyuridine incorporation. The increase in wall thickness is reminiscent of the arterial thickening seen in human hypertension and atherosclerosis. Similar results were reported by Moroi et al. (Moroi et al., 1998Moroi M Zhang L Yasuda T Virmani R Gold HK Fishman MC Huang PL Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice.J Clin Invest. 1998; 101: 1225-1232Crossref PubMed Scopus (282) Google Scholar), using an injury model initiated by a vascular cuff placed around the femoral artery of wild type or eNOS knockout mice (Moroi et al. Moroi et al., 1998Moroi M Zhang L Yasuda T Virmani R Gold HK Fishman MC Huang PL Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice.J Clin Invest. 1998; 101: 1225-1232Crossref PubMed Scopus (282) Google Scholar). This treatment causes marked intimal proliferation for both genotypes, but the response was greatly exaggerated in eNOS knockout mice. Finally, in studies of ischemic angiogenesis and remodeling, eNOS knockout mice did not revascularize to the same extent as did wild type mice after hindlimb ischemia. Moreover, administration of vascular endothelial growth factor (VEGF) increased capillary density in wild type mice, but not in eNOS-deficient mice, supporting the idea that VEGF uses NO as a critical second messenger for endothelial cell phenotypes associated with angiogenesis (Ziche et al. Ziche et al., 1994Ziche M Morbidelli L Masini E Amerini S Granger HJ Maggi CA Geppetti P et al.Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P.J Clin Invest. 1994; 94: 2036-2044Crossref PubMed Scopus (747) Google Scholar; Papapetropoulos et al. Papapetropoulos et al., 1997Papapetropoulos A Garcia-Cardena G Madri JA Sessa WC Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells.J Clin Invest. 1997; 100: 3131-3139Crossref PubMed Scopus (983) Google Scholar). Collectively, results of these studies indicate that eNOS is critical to coupling luminal hemodynamics to a remodeling response, and they imply that NO is likely the major factor produced by the endothelium required for physiological remodeling as originally described by Langille and O'Donnell (Langille and O'Donnell, 1986Langille BL O'Donnell F Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent.Science. 1986; 231: 405-407Crossref PubMed Scopus (899) Google Scholar). The strong relationship between endothelial dysfunction and abnormal vascular remodeling is a prominent feature of many cardiovascular diseases. Endothelium-derived NO is a powerful regulator of vascular function, and it appears that abnormalities in the production or actions of NO lead to endothelial dysfunction and abnormal vascular remodeling. The lack of linkage between eNOS and the disease phenotypes analyzed thus far argues against a simple model in which eNOS mutations directly cause heritable vascular disease, but it is possible that further analysis of identified polymorphisms may show significant vascular phenotypes.