Resistance Arteries In Hypertension Research Articles

Vascular Smooth Muscle Remodeling in Conductive and Resistance Arteries in Hypertension.

Cardiovascular disease is a leading cause of death worldwide and accounts for >17.3 million deaths per year, with an estimated increase in incidence to 23.6 million by 2030. 1 Cardiovascular death represents 31% of all global deaths 2 -with stroke, heart attack, and ruptured aneurysms predominantly contributing to these high mortality rates. A key risk factor for cardiovascular disease is hypertension. Although treatment or reduction in hypertension can prevent the onset of cardiovascular events, existing therapies are only partially effective. A key pathological hallmark of hypertension is increased peripheral vascular resistance because of structural and functional changes in large (conductive) and small (resistance) arteries. In this review, we discuss the clinical implications of vascular remodeling, compare the differences between vascular smooth muscle cell remodeling in conductive and resistance arteries, discuss the genetic factors associated with vascular smooth muscle cell function in hypertensive patients, and provide a prospective assessment of current and future research and pharmacological targets for the treatment of hypertension.

Inositol 1,4,5-Trisphosphate Receptors in Hypertension.

Chronic hypertension remains a major cause of global mortality and morbidity. It is a complex disease that is the clinical manifestation of multiple genetic, environmental, nutritional, hormonal, and aging-related disorders. Evidence supports a role for vascular aging in the development of hypertension involving an impairment in endothelial function together with an alteration in vascular smooth muscle cells (VSMCs) calcium homeostasis leading to increased myogenic tone. Changes in free intracellular calcium levels ([Ca2+]i) are mediated either by the influx of Ca2+ from the extracellular space or release of Ca2+ from intracellular stores, mainly the sarcoplasmic reticulum (SR). The influx of extracellular Ca2+ occurs primarily through voltage-gated Ca2+ channels (VGCCs), store-operated Ca2+ channels (SOC), and Ca2+ release-activated channels (CRAC), whereas SR-Ca2+ release occurs through inositol trisphosphate receptor (IP3R) and ryanodine receptors (RyRs). IP3R-mediated SR-Ca2+ release, in the form of Ca2+ waves, not only contributes to VSMC contraction and regulates VGCC function but is also intimately involved in structural remodeling of resistance arteries in hypertension. This involves a phenotypic switch of VSMCs as well as an alteration of cytoplasmic Ca2+ signaling machinery, a phenomena tightly related to the aging process. Several lines of evidence implicate changes in expression/function levels of IP3R isoforms in the development of hypertension, VSMC phenotypic switch, and vascular aging. The present review discusses the current knowledge of these mechanisms in an integrative approach and further suggests potential new targets for hypertension management and treatment.

Endothelium-derived Relaxing Factors of Small Resistance Arteries in Hypertension.

Endothelium-derived relaxing factors (EDRFs), including nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF), play pivotal roles in regulating vascular tone. Reduced EDRFs cause impaired endothelium-dependent vasorelaxation, or endothelial dysfunction. Impaired endothelium-dependent vasorelaxation in response to acetylcholine (ACh) is consistently observed in conduit vessels in human patients and experimental animal models of hypertension. Because small resistance arteries are known to produce more than one type of EDRF, the mechanism(s) mediating endothelium-dependent vasorelaxation in small resistance arteries may be different from that observed in conduit vessels under hypertensive conditions, where vasorelaxation is mainly dependent on NO. EDHF has been described as one of the principal mediators of endothelium-dependent vasorelaxation in small resistance arteries in normotensive animals. Furthermore, EDHF appears to become the predominant endothelium-dependent vasorelaxation pathway when the endothelial NO synthase (NOS3)/NO pathway is absent, as in NOS3-knockout mice, whereas some studies have shown that the EDHF pathway is dysfunctional in experimental models of hypertension. This article reviews our current knowledge regarding EDRFs in small arteries under normotensive and hypertensive conditions.

Effect of treatment on cardiac small resistance arteries in hypertension and diabetes

Effect of treatment on cardiac small resistance arteries in hypertension and diabetes

Inward remodeling of resistance arteries requires reactive oxygen species-dependent activation of matrix metalloproteinases

Inward eutrophic remodeling is the most prevalent structural change of resistance arteries in hypertension. Sympathetic and angiotensin (ANG)-induced vasoconstriction has been associated with hypertension and with the production of matrix metalloproteinases (MMPs) and ROS. Therefore, we hypothesize that prolonged exposure to norepinephrine (NE) and ANG II induces arteriolar inward remodeling dependent on the activation of MMPs and the production of ROS. This hypothesis was tested on rat cremaster arterioles that were isolated, cannulated, pressurized, and exposed to either NE (10(-5.5) mol/l) + ANG II (10(-7) mol/l) or vehicle (control) for 4 h. The prolonged exposure to NE + ANG II induced inward remodeling, as evidenced by the reduced maximal arteriolar passive diameter observed after versus before exposure to the vasoconstrictor agonists. NE + ANG II also increased the arteriolar expression and activity of MMP-2 and the production of ROS as determined, respectively, by real-time RT-PCR, gel and in situ zymography, and the use of ROS-sensitive dyes with multiphoton microscopy. Inhibition of MMP activation (with GM-6001) or ROS production (with apocynin or tempol) prevented the NE + ANG II-induced inward remodeling. Inhibition of ROS production prevented the activation of MMPs and the remodeling process, whereas inhibition of MMP activation did not affect ROS production. These results indicate that prolonged stimulation of resistance arterioles with NE + ANG II induces a ROS-dependent activation of MMPs necessary for the development of arteriolar inward remodeling. These mechanisms may contribute to the structural narrowing of resistance vessels in hypertension.

Mechanism(s) of Systolic Blood Pressure Reduction and Drug Therapy in Hypertension

Antihypertensive drug therapy is a major modality of cardiovascular (CV) disease prevention, especially for stroke, congestive heart failure, and renal insufficiency. Coronary risk is also consistently prevented by antihypertensive treatment, but to a lesser extent.1–4 The Prime Study2 has shown that drug-induced blood pressure (BP) reduction in hypertensive subjects is associated with a significant decrease of coronary risk. However, when treated and untreated subjects are compared, at any given value of systolic BP (SBP), this risk remains higher in treated than in untreated subjects, suggesting the persistence of residual coronary complications. Results of therapeutic trials also indicate that coronary risk is associated with a particular hemodynamic pattern in treated hypertensive subjects.3 Although diastolic BP (DBP) is significantly lowered by drug treatment to <90 mm Hg (80% of the patients), SBP remains above 140 mm Hg in 60%, indicating an increase of pulse pressure (PP), which is the difference between SBP and DBP.4 It is widely accepted that SBP and PP rise sharply with age and that this increase is a major manifestation of vascular aging and stiffening, which are now considered major predictors of CV risk, independent of the mean BP (MBP) level.4 The purpose of this review is to analyze the mechanism(s) of SBP in untreated and chronically treated hypertensive subjects and to determine which pathophysiological factors are susceptible to attenuating consistently coronary and CV complications in hypertensive populations. Ventricular ejection in humans is associated with 2 principal events. First, the coronary circulation is transiently interrupted, as the principal consequence of cardiac contraction, and, second, an acute shock of stroke volume against the aortic wall is observed (Figure 1). Then, the BP curve may be considered as a wave, which travels along the arterial tree at a given speed, the pulse wave velocity (PWV). …

Smad3 Mediates Angiotensin II– and TGF-β1–Induced Vascular Fibrosis

See related article, pages 1032–1039 Hypertension, diabetes, and atherosclerosis are three diseases responsible for the majority of cardiovascular morbidity in humans. Not only are they independent risk factors, but they clearly potentiate and complement each other in the pathogenesis of cardiovascular disease. The first manifestation of end-organ damage in these diseases is the vascular remodeling of small (resistance) and large (conductance), and this precedes the development of cardiac hypertrophy, renal insufficiency or stroke.1 This vascular remodeling is characterized by hyperplasia, hypertrophy, and apoptosis of smooth muscle cells (SMCs) and vascular fibrosis, caused by increased extracellular matrix deposition of total collagen, and changes in ratio of type I/III collagen, fibronectin, and proteoglycans.1 Angiotensin II (Ang II) has recently emerged as a key mediator of vascular fibrosis (sclerosis) both in humans and animal models of hypertension because of its pleiotropic effects of SMCs, fibroblasts, and inflammatory cells. Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonists (ARB) diminish cardiac hypertrophy and vascular fibrosis in animal models of hypertension.1,2 In human clinical trials of hypertension, ARBs reverse vascular remodeling in resistance arteries and new incidence of strokes more potently than any other antihypertensive agents (beta-blockers or calcium channel blockers), despite similar reduction in blood pressure.3,4 This provides strong evidence that targeting the mechanisms involved in arterial remodeling process may provide the key in preventing the long-term consequences of hypertension or atherosclerosis in humans. However, deciphering the intimate mechanisms of in vivo vascular remodeling has become very complex because of enormous reciprocal interactions between Ang II and other growth factors. Ang II exerts its effects not only by activating its specific receptors, but also by transactivating other growth factor receptors such as epidermal growth factor …

New aspects of artery resistance and structure

This issue contains a series of papers by the speakers at a Physiological Society sponsored symposium that took place during the meeting of the Spanish Physiological Society in Seville on February 13th 2005. The theme of the symposium was the need to consider the interaction between different components of the vascular wall in maintaining the structure of a blood vessel. The four speakers tackled topics ranging across the different cell types, their interactions and the signalling cascades involved. Rhian Touyz (Montreal) sets the scene with a presentation of the Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: the role of angiotensin II (Touyz, 2005). She reviews the signalling pathways in arterial smooth muscle cells and describes her laboratory's work in elucidating angiotensin II-mediated signalling, pointing out that we still know little about the specific molecules that underlie aberrant signalling in hypertension or at what level some cascades become more important than others. Ana Fortuño (Pamplona) addresses Oxidative stress and vascular remodelling (Fortuño et al. 2005), focusing on the pathophysiology of vascular diseases and how increased production of reactive oxygen species contributes to oxidative stress and is implicated in pathological processes, including endothelial dysfunction, activation of matrix metalloproteinases and smooth muscle cell migration, growth and apoptosis. She discusses NADPH oxidase as the most important source of superoxide anion in phagocytic and vascular cells. Silvia Arribas (Madrid) emphasises the importance of extracellular structures in maintaining arterial function, particularly Influence of elastin on rat small artery mechanical properties (González et al. 2005). She reviews how elastin gene defects and knock-out mice have highlighted the importance of elastin in vascular morphogenesis and hypothesises that it might also be critical in the vascular remodelling in diseases related to haemodynamic stress. She describes studies in the spontaneously hypertensive rat, in which elastin has a quite different organization from elastin in normotensive control animals, having an internal elastic lamina with smaller fenestrae, and she considers how early alterations in elastin might be key events in the inward remodelling in hypertension. The series is rounded off by Ian McGrath (Glasgow), who summarises New aspects of vascular remodelling: the involvement of all vascular cell types (McGrath et al. 2005), emphasising the roles of adventitia and endothelium as key players in vascular growth and repair, and painting a picture of blood vessels as in a constant state of self-maintenance. He also considers how new locations of receptors for vasoactive hormones shown by confocal microscopy and fluorescent ligands suggest new concepts in the on-going regulation of vascular structure.

Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: role of angiotensin II

Resistance arteries undergo structural changes (vascular remodelling) in hypertension. These changes involve media thickening, reduced lumen diameter and consequent increased media:lumen ratio. Cellular processes underlying these events include altered vascular smooth muscle cell (VSMC) growth, migration, differentiation and increased extracellular matrix abundance. Another factor contributing to remodelling is inflammation, associated with macrophage infiltration, fibrosis and increased expression of redox-sensitive pro-inflammatory genes. Among the factors involved in arterial remodelling, angiotensin (Ang) II appears to be one of the most important. Ang II, a multifunctional peptide with pleiotropic actions, modulates vasomotor tone, cell growth, apoptosis/anoikis, cell migration and extracellular matrix deposition. It is pro-inflammatory and it stimulates production of growth factors and vasoactive agents. The multiple actions of Ang II are mediated via complex intracellular signalling pathways including stimulation of the phosholipase C (PLC)-inositol 1,4,5-trisphosphate (IP3)-1,2-diacylglycerol (DAG) cascade, mitogen-activated protein (MAP) kinases, tyrosine kinases and RhoA/Rho kinase. Furthermore, Ang II elicits many of its (patho)physiological effects by stimulating reactive oxygen species (*O2- and H2O2) generation through activation of vascular NAD(P)H oxidase. *O2- and H2O2 in turn influence downstream signalling molecules including transcription factors, tyrosine kinases/phosphatases, Ca2+ channels and MAP kinases. Interaction between these systems is complex and dysregulation at any level may contribute to vascular remodelling. Targeting such molecules/pathways could prevent or induce regression of hypertensive vascular damage thereby ameliorating development of hypertension and preventing target organ damage. The present review discusses the role of Ang II in remodelling of resistance arteries, focusing on some signalling pathways involved in vascular growth and inflammation in hypertension.

From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension.

resistance arteries are vessels of ∼100–300 μm in lumen diameter that are an important site of resistance to blood flow. Small artery-dependent increased peripheral resistance may participate in development and complications of hypertension. The degree of remodeling of small arteries has

Structure and mechanical properties of resistance arteries in hypertension: role of adhesion molecules and extracellular matrix determinants.

Abnormalities of resistance arteries may play a role in the pathogenesis and pathophysiology of hypertension in experimental animals and humans. Vessels that, when relaxed, measure <400 microm in lumen diameter act as the major site of vascular resistance and include a network of small arteries (lumen approximately 100 to 400 microm) and arterioles (<100 microm). Because increased peripheral resistance is generated by a narrowed lumen diameter, significant effort has been focused on determining the mechanisms that reduce lumen size. Three important vascular components are clearly involved, including alterations of vascular structure, mechanics (stiffness), and function. Structural abnormalities comprise a reduced lumen diameter and thickening of the vascular media, resulting in an increased media-lumen ratio. Changes in the mechanical properties of an artery, particularly increased stiffness, may also result in a reduced lumen diameter. These vascular abnormalities may be caused or influenced by the expression and/or topographic localization of extracellular matrix components, such as collagen and elastin, and by changes in cell-extracellular fibrillar attachment sites, such as adhesion molecules like integrins. This article discusses the abnormalities of resistance arteries in hypertension and reviews the evidence suggesting an important role for adhesive and extracellular matrix determinants.

Remodeling of Resistance Arteries in Human Hypertension: Effects of Cilazapril, an Angiotensin- I -Converting Enzyme Inhibitor

Studies on the effect of antihypertensive agents on resistance arteries in hypertensive patients have in the past yielded inconclusive results regarding the ability of these drugs to induce a regression toward normal of either the structure or the function of these critically important vessels. We have recently compared the effects of the angiotensin-I-converting enzyme inhibitor cilazapril and of the beta blocker atenolol on the structure and the function of subcutaneous resistance arteries of essential hypertensive patients. The patients were randomly assigned to receive either cilazapril or atenolol for a period of 2 years. The blood pressure was normalized for the duration of the trial by both drugs. The media-to-lumen ratio of resistance arteries, which was significantly increased in all hypertensive patients before starting treatment, was normalized by the 2-year treatment with cilazapril, whereas treatment with atenolol did not result in any change in this vascular parameter. Treatment with cilazapril also returned to normal the contractile responses to several vasoconstrictors, particularly endothelin 1. Endothelium-dependent relaxation responses of blood vessels to acetylcholine were abnormal in hypertensive patients and improved in the cilazapril-treated patients, but remained unchanged in the atenolol-treated ones. We conclude that treatment with the angiotensin-I-converting enzyme inhibitor cilazapril corrects in part the vascular remodeling and the functional abnormalities of resistance arteries of hypertensive patients, whereas treatment with the beta blocker atenolol does not. These results may indicate that treatment with cilazapril and perhaps with other angiotensin-I-converting enzyme inhibitors as well may improve the clinical outcome in hypertension by inducing a regression of abnormal resistance vessel structure and function.

Endothelium-Derived Relaxing Factor and Endothelin in Hypertension

In resistance arteries, endothelium-derived nitric oxide inhibits vasoconstrictors;this and endothelium-dependent relaxations to acetylcholine are blunted in hypertension. The sensitivity of hypertensive resistance arteries with endothelium to intraluminal endothelin-1 is normal but is reduced without endothelium. Thus hypertension impairs endothelial regulation of the resistance circulation.

38. Endogenous endothelin stimulated by angiotensin II augments contractility of hypertensive resistance arteries

38. Endogenous endothelin stimulated by angiotensin II augments contractility of hypertensive resistance arteries

Endothelin in hypertensive resistance arteries. Intraluminal and extraluminal dysfunction.

The effects of intraluminal and extraluminal endothelin-1 and its interactions with endothelium-derived relaxing factor were studied in perfused mesenteric resistance arteries of Wistar-Kyoto rats and spontaneously hypertensive rats. Changes in intraluminal diameter were recorded. In adult Wistar-Kyoto rats, but not spontaneously hypertensive rats, low concentrations of intraluminal endothelin-1 (10(-10) to 10(-9) M) caused relaxations of quiescent arteries blocked by indomethacin. After endothelial removal, intraluminal endothelin-1 evoked concentration-dependent contractions in both strains. Extraluminal endothelin-1 caused greater contractions of arteries with endothelium than intraluminal endothelin-1, and the sensitivity was lower in adult hypertensive rats; endothelial removal enhanced the contractions to extraluminal endothelin-1 to a greater extent in hypertensive than in normotensive rats. In arteries without endothelium, intraluminal and extraluminal endothelin-1 caused comparable contractions, but the sensitivity was reduced in adult but not young hypertensive as compared with normotensive rats. Both young spontaneously hypertensive and normotensive rats exhibited a high sensitivity to the peptide. In arteries precontracted with endothelin-1, endothelium-dependent relaxation to intraluminal acetylcholine was reduced in hypertensive as compared with normotensive rats, whereas relaxations to extraluminal acetylcholine were increased in hypertensive rats. Thus, endothelin-1 interacts with both vascular smooth muscle and the endothelium. The sensitivity of vascular smooth muscle to endothelin-1 is reduced in adult hypertensive rats. Intraluminal activation of the endothelium by endothelin-1 or acetylcholine is reduced in spontaneously hypertensive rats, whereas extraluminal activation causes more pronounced responses in hypertensive than in normotensive rats, suggesting a prominent dysfunction of the intraluminal surface of the endothelium in hypertension.

38. Endogenous endothelin stimulated by angiotensin II augments contractility of hypertensive resistance arteries

38. Endogenous endothelin stimulated by angiotensin II augments contractility of hypertensive resistance arteries

Impaired endothelium-dependent relaxations in hypertensive resistance arteries involve cyclooxygenase pathway

Endothelial cells modulate vascular tone by releasing endothelium-derived relaxing (EDRF) and contracting factors. An imbalance of these factors in hypertension could contribute to increased peripheral vascular resistance. Mesenteric resistance arteries of Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) were suspended in a myograph filled with physiological salt solution (37 degrees C; 95% O2-5% CO2). In WKY rings contracted with norepinephrine, acetylcholine (10(-9)-10(-4) M) evoked endothelium-dependent relaxations (88 +/- 2%, IC50 7.3 +/- 0.1; n = 31). Hemoglobin (10(-5) M) but not meclofenamate (10(-5) M) reversed the relaxations delineating EDRF as the mediator. Nitric oxide (3 X 10(-9)-10(-5) M) induced comparable relaxations as acetylcholine. In SHRSP, relaxations to acetylcholine but not those to nitric oxide were impaired (61 +/- 5%, IC50 greater than 6.6 +/- 0.4; n = 24; P less than 0.005). In SHRSP, meclofenamate but not the thromboxane synthetase inhibitor CGS 13080 normalized endothelium-dependent relaxations. Relaxations to sodium nitroprusside were enhanced in SHRSP both in rings with and without endothelium. Thus our results are compatible with the concept that endothelium-dependent relaxations in resistance arteries are mediated by nitric oxide. In SHRSP, endothelium-dependent relaxations are impaired because of a cyclooxygenase-dependent substance interfering with the release and/or action of EDRF.

Changes to the Vascular System Resulting from Hypertension and Their Effects on Response to Therapy

This review is concerned with the structure and function of resistance arteries in hypertension. By use of a variety of techniques, results indicate that raised blood pressure, in patients with essential hypertension and in animal models of hypertension, is associated with abnormalities in the structure of small arteries, expressed as an increased media: lumen ratio and reduced lumen. Functional changes, expressed as an increased sensitivity of resistance arteries to various agonists, have been seen in the spontaneously hypertensive rat, but there is no evidence for such increased sensitivity of resistance arteries in patients with essential hypertension. The role of resistance artery structural abnormalities in the long term control of peripheral resistance is not clear. On the one hand, resistance artery structure appears to be determined by the factors which produce the hypertension, both directly through neurohumoral influences and indirectly through the resulting raised intravascular pressure. On the other hand, the limited experimental evidence available suggests that small artery structure does not have a dominating effect on blood pressure and thus on the control of peripheral resistance. Furthermore, once produced, it is difficult to obtain regression of an abnormal structure. These results suggest that small artery structure is determined primarily by the prevailing intravascular pressure and the mechanisms which produce it. It is still not clear if small artery structure in itself is a major controller of peripheral resistance, but it appears that the effects of altered small artery structure may be overridden by extravascular factors.