Hypertensive Vascular Remodeling Research Articles

Time course involvement of matrix metalloproteinases in the vascular alterations of renovascular hypertension

Increased vascular matrix metalloproteinases (MMPs) levels play a role in late phases of hypertensive vascular remodeling. However, no previous study has examined the time course of MMPs in the various phases of two-kidney, one-clip hypertension (2K1C). We examined structural vascular changes, collagen and elastin content, vascular oxidative stress, and MMPs levels/activities during the development of 2K1C hypertension. Plasma angiotensin converting enzyme (ACE) activity was measured to assess renin-angiotensin system activation. Sham or 2K1C hypertensive rats were studied after 2, 4, 6, and 10weeks of hypertension. Systolic blood pressure (SBP) was monitored weekly. Morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin, orcein and picrosirius red sections. Aortic NADPH activity and superoxide production was evaluated. Aortic gelatinolytic activity was determined by in situ zymography, and MMP-2, MMP-14, and tissue inhibitor of MMPs (TIMP)-2 levels were determined by gelatin zymography, immunofluorescence and immunohistochemistry. 2K1C hypertension was associated with increased ACE activity, which decreased to normal after 10weeks. We found increased aortic collagen and elastin content in the early phase of hypertension, which were associated with vascular hypertrophy, increased vascular MMP-2 and MMP-14 (but not TIMP-2) levels, and increased gelatinolytic activity, possibly as a result of increased vascular NADPH oxidase activity and oxidative stress. These results indicate that vascular remodeling of renovascular hypertension is an early process associated with early increases in MMPs activities, enhanced matrix deposition and oxidative stress. Using antioxidants or MMPs inhibitors in the early phase of hypertension may prevent the vascular alterations of hypertension.

A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects

Many chronic pulmonary diseases are associated with pulmonary hypertension (PH) and pulmonary vascular remodeling, which is a term that continues to be used to describe a wide spectrum of vascular abnormalities. Pulmonary vascular structural changes frequently increase pulmonary vascular resistance, causing PH and right heart failure. Although rat models had been standard models of PH research, in more recent years the availability of genetically engineered mice has made this species attractive for many investigators. Here we review a large amount of data derived from experimental PH reports published since 1996. These studies using wild-type and genetically designed mice illustrate the challenges and opportunities provided by these models. Hemodynamic measurements are difficult to obtain in mice, and right heart failure has not been investigated in mice. Anatomical, cellular, and genetic differences distinguish mice and rats, and pharmacogenomics may explain the degree of PH and the particular mode of pulmonary vascular adaptation and also the response of the right ventricle.

The Mechanisms for the Progression of Hypertensive Heart Disease to Heart Failure

Affecting 40 million Japanese, systemic hypertension remains a major public health problem associated with considerable morbidity and mortality. Hypertension clearly damages the cardiac and vascular systems over time, causing hypertensive heart disease, renal dysfunction and vascular remodeling. Hypertensive heart disease is a constellation of abnormalities that includes left ventricular hypertrophy (LVH), systolic and diastolic dysfunction, and their clinical manifestations including arrhythmias and symptomatic heart failure.

Myoendothelial gap junctional signaling induces differentiation of pulmonary arterial smooth muscle cells

Myoendothelial gap junctions are involved in regulating systemic arterial smooth muscle cell phenotype and function, but their role in the regulation of pulmonary arterial smooth muscle cell (PASMC) phenotype is unknown. We therefore investigated in cocultured pulmonary arterial endothelial cells (PAECs) and PASMCs whether myoendothelial gap junctional signaling played a role in PAEC-dependent regulation of PASMC phenotype. Rat PAECs and PASMCs were cocultured on opposite sides of a porous Transwell membrane that permitted formation of heterotypic cell-cell contacts. Immunostaining showed expression of the gap junctional protein connexin 43 (Cx43) on projections extending into the membrane from both cell types. Dye transfer exhibited functional gap junctional communication from PAECs to PASMCs. PASMCs cocultured with PAECs had a more contractile-like phenotype (spindle shape and increased expression of the contractile proteins myosin heavy chain, H1-calponin, and α-smooth muscle cell-actin) than PASMCs cocultured with PASMCs or cocultured without direct contact with PAECs. Transforming growth factor (TGF)-β1 signaling was activated in PASMCs cocultured with PAECs, and the PASMC differentiation was inhibited by TGF-β type I receptor blockade. Inhibition of gap junctional communication pharmacologically or by knock down of Cx43 in PAECs blocked TGF-β signaling and PASMC differentiation. These results implicate myoendothelial gap junctions as a gateway for PAEC-derived signals required for maintaining TGF-β-dependent PASMC differentiation. This study identifies an alternative pathway to paracrine signaling to convey regulatory signals from PAECs to PASMCs and raises the possibility that dysregulation of this direct interaction is involved in the pathogenesis of hypertensive pulmonary vascular remodeling.

MicroRNA-130a Mediates Proliferation of Vascular Smooth Muscle Cells in Hypertension

It has been reported that microRNA-130a (miR-130a) targets GAX, the growth arrest-specific homeobox, which inhibits proliferation, differentiation, and migration of vascular smooth muscle cells (VSMCs). In the present study, we therefore investigated the effect of miR-130a on proliferation of cultured VSMCs and the potential role of miR-130a in vascular remodeling during hypertension. Proliferation of VSMCs was determined by 5-bromo-2'-deoxyuridine (BrdU) incorporation method. The expression of miR-130a and GAX was analyzed by quantitative reverse transcription-PCR. The protein expression of GAX was analyzed by western blot. The mimic and inhibitor of miR-130a were used in gain-of-function and loss-of-function in vitro studies, respectively. The correlation of miR-130a with vascular remodeling was observed in spontaneously hypertensive rats (SHRs). MiR-130a mimic at the concentration of 25 or 50 nmol/l significantly promoted proliferation of VSMCs. The expression of miR-130a was upregulated in the remodeled aorta and superior mesenteric artery of SHRs. The expression of GAX was downregulated in VSMCs transfected with miR-130a mimic and in thoracic aorta and superior mesenteric artery of SHRs. Angiotensin II (Ang II) promoted proliferation of VSMCs and upregulated miR-130a expression concomitantly with a decreased GAX expression in a concentration- and time-dependent manner. The proliferative effects of Ang II on VSMCs were suppressed partly by the miR-130a inhibitor. These results suggest that miR-130a is a novel regulator of proliferation of VSMCs via inhibiting the expression of GAX, which may contribute to vascular remodeling in hypertension.

Involvement of profilin-1 in angiotensin II-induced vascular smooth muscle cell proliferation

Profilin-1, a regulator of actin polymerization, has recently been linked to vascular hypertrophy and remodeling. Whether profilin-1 is involved in angiotensin (Ang) II-induced proliferation of vascular smooth muscle cells leading to vascular remodeling in hypertension remains unclear. The present study was designed to analyze the correlation of profilin-1 and vascular remodeling during hypertension and to evaluate the role of profilin-1 in proliferation of vascular smooth muscle cells and the underlying mechanisms. The vascular morphology and the expression of profilin-1 in arterial tissues of spontaneously hypertensive rats and Wistar–Kyoto rats were assessed. The profilin-1 expression was significantly increased concomitantly with definite vascular remodeling by evaluating the media thickness, lumen diameter, media thickness-to-lumen diameter ratio and mean nuclear area in artery media in spontaneously hypertensive rats, which was inhibited by treatment with losartan. In cultured rat aortic smooth muscle cells (RASMCs), Ang II induced profilin-1 expression in a dose- and time-dependent manner. Knockdown of profilin-1 using small hairpin RNA inhibited Ang II-induced proliferation of RASMCs. Moreover, blockade of JAK2/STAT3 signaling pathway also inhibited Ang II-induced proliferation of RASMCs and profilin-1 expression. These results suggest that profilin-1 mediates the proliferation of RASMCs induced by Ang II via activation of Ang II type 1 receptor/JAK2/STAT3 signaling pathway, which may contribute to vascular remodeling in hypertension.

Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats

Matrix metalloproteases (MMPs) are a family of zinc peptidases involved in extracellular matrix turnover. There is evidence that increased MMP activity is involved in remodeling of resistance vessels in chronic hypertension. Thus we hypothesized that inhibition of MMP activity with doxycycline (DOX) would attenuate vascular remodeling. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with DOX (50 mg·kg(-1)·day(-1) in the drinking water) for 6 wk. Untreated SHRSP were controls. Blood pressure was measured by telemetry during the last week. Middle cerebral artery (MCA) and mesenteric resistance artery (MRA) passive structures were assessed by pressure myography. MMP-2 expression in aortas was measured by Western blot. All results are means ± SE. DOX caused a small increase in mean arterial pressure (SHRSP, 154 ± 1; SHRSP + DOX, 159 ± 3 mmHg; P < 0.001). Active MMP-2 expression was reduced in aorta from SHRSP + DOX (0.21 ± 0.06 vs. 0.49 ± 0.13 arbitrary units; P < 0.05). In the MCA, at 80 mmHg, DOX treatment increased the lumen (273.2 ± 4.7 vs. 238.3 ± 6.3 μm; P < 0.05) and the outer diameter (321 ± 5.3 vs. 290 ± 7.6 μm; P < 0.05) and reduced the wall-to-lumen ratio (0.09 ± 0.002 vs. 0.11 ± 0.003; P < 0.05). Damage after transient cerebral ischemia (transient MCA occlusion) was reduced in SHRSP + DOX (20.7 ± 4 vs. 45.5 ± 5% of hemisphere infarcted; P < 0.05). In the MRA, at 90 mmHg DOX, reduced wall thickness (29 ± 1 vs. 22 ± 1 μm; P < 0.001) and wall-to-lumen ratio (0.08 ± 0.004 vs. 0.11 ± 0.008; P < 0.05) without changing lumen diameter. These results suggest that MMPs are involved in hypertensive vascular remodeling in both the peripheral and cerebral vasculature and that DOX reduced brain damage after cerebral ischemia.

Involvement of vascular peroxidase 1 in angiotensin II-induced vascular smooth muscle cell proliferation

Vascular peroxidase 1 (VPO1) is a newly identified haem-containing peroxidase that catalyses the oxidation of a variety of substrates by hydrogen peroxide (H(2)O(2)). Considering the well-defined effects of H(2)O(2) on the vascular remodelling during hypertension, and that VPO1 can utilize H(2)O(2) generated from co-expressed NADPH oxidases to catalyse peroxidative reactions, the aims of this study were to determine the potential role of VPO1 in vascular remodelling during hypertension. The vascular morphology and the expression of VPO1 in arterial tissues of spontaneously hypertensive rats and Wistar-Kyoto rats were assessed. The VPO1 expression was significantly increased concomitantly with definite vascular remodelling assessed by evaluating the media thickness, lumen diameter, media thickness-to-lumen diameter ratio and mean nuclear area in artery media in spontaneously hypertensive rats. In addition, in cultured rat aortic smooth muscle cells we found that the angiotensin II-mediated cell proliferation was inhibited by knockdown of VPO1 using small hairpin RNA. Moreover, the NADPH oxidase inhibitor, apocynin, and the hydrogen peroxide scavenger, catalase, but not the ERK1/2 inhibitor, PD98059, attenuated angiotensin II-mediated up-regulation of VPO1 and generation of hypochlorous acid. VPO1 is a novel regulator of vascular smooth muscle cell proliferation via NADPH oxidase-H(2)O(2)-VPO1-hypochlorous acid-ERK1/2 pathways, which may contribute to vascular remodelling in hypertension.

Angiotensin II Type 1A Receptors in Vascular Smooth Muscle Cells Do Not Influence Aortic Remodeling in Hypertension

Vascular injury and remodeling are common pathological sequelae of hypertension. Previous studies have suggested that the renin-angiotensin system acting through the type 1 angiotensin II (AT(1)) receptor promotes vascular pathology in hypertension. To study the role of AT(1) receptors in this process, we generated mice with cell-specific deletion of AT(1) receptors in vascular smooth muscle cells using Cre/Loxp technology. We crossed the SM22α-Cre transgenic mouse line expressing Cre recombinase in smooth muscle cells with a mouse line bearing a conditional allele of the Agtr1a gene (Agtr1a (flox)), encoding the major murine AT(1) receptor isoform (AT(1A)). In SM22α-Cre(+)Agtr1a (flox/flox) (SMKO) mice, AT(1A) receptors were efficiently deleted from vascular smooth muscle cells in larger vessels but not from resistance vessels such as preglomerular arterioles. Thus, vasoconstrictor responses to angiotensin II were preserved in SMKO mice. To induce hypertensive vascular remodeling, mice were continuously infused with angiotensin II for 4 weeks. During infusion of angiotensin II, blood pressures increased significantly and to a similar extent in SMKO and control mice. In control mice, there was evidence of vascular oxidative stress indicated by enhanced nitrated tyrosine residues in segments of aorta; this was significantly attenuated in SMKO mice. Despite these differences in oxidative stress, the extent of aortic medial expansion induced by angiotensin II infusion was virtually identical in both groups. Thus, vascular AT(1A) receptors promote oxidative stress in the aortic wall but are not required for remodeling in angiotensin II-dependent hypertension.

Role of Elastic Fibers on Cardiovascular Disease

An important factor in the transition from an open to a closed circulatory system was a change in vessel wall that are dynamic structure composed of cells and extracellular matrix. The component of arterial wall in vertebrates that accounts for these properties is the elastic fiber network organized by medial smooth muscle cells. Elastin and elastin associated protein are synthesized and secreted by vascular smooth muscle cells and are the major extracellular matrix component deposited in the vascular wall. Pathological states related to hypertension or atherosclerosis is associated with vascular wall remodeling, which is deleterious for cardiovascular function. Elastic fiber may be key factors in the pathophysiology of hypertensive or atherosclerotic vascular remodeling. The well-known effects of cardiovascular disease on the deterioration and the promoted degradation of elastic fiber result to loss of arterial wall resilience. Recently, several studies have highlighted new roles for individual components of elastic fiber and their degraded products. This review describes current knowledge regarding components of elastic fibers and discusses relationship between their structural abnormalities and cardiovascular diseases.

Comparative study on antioxidant effects and vascular matrix metalloproteinase-2 downregulation by dihydropyridines in renovascular hypertension

The vascular remodeling associated with hypertension involves oxidative stress and enhanced matrix metalloproteinases (MMPs) expression/activity, especially MMP-2. While previous work showed that lercanidipine, a third-generation dihydropyridine calcium channel blocker (CCB), attenuated the oxidative stress and increased MMP-2 expression/activity in two-kidney, one-clip (2K1C) hypertension, no previous study has examined whether first- or second-generation dihydropyridines produce similar effects. We compared the effects of nifedipine, nimodipine, and amlodipine on 2K1C hypertension-induced changes in systolic blood pressure (SBP), vascular remodeling, oxidative stress, and MMPs levels/activity. Sham-operated and 2K1C rats were treated with water, nifedipine 10 mg/kg/day, nimodipine 15 mg/kg/day, or amlodipine 10 mg/kg/day by gavage, starting 3 weeks after hypertension was induced. SBP was monitored weekly. After 6 weeks of treatment, quantitative morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin-stained sections. Aortic and systemic reactive oxygen species levels were measured by using dihydroethidine and thiobarbituric acid-reactive substances (TBARs), respectively. Aortic MMP-2 levels and activity were determined by gelatin zymography, in situ zymography, and immunofluorescence. Nifedipine, nimodipine, or amlodipine attenuated the increases in SBP in hypertensive rats by approximately 17% (P < 0.05) and prevented vascular hypertrophy (P < 0.05). These CCBs blunted 2K1C-induced increases in vascular oxidative stress and plasma TBARs concentrations (P < 0.05). All dihydropyridines attenuated the increases in aortic MMP-2 levels and activity associated with 2K1C hypertension. These findings suggest lack of superiority of one particular dihydropyridine, at least with respect to antioxidant effects, MMPs downregulation, and inhibition of vascular remodeling in hypertension.

Reactive oxygen species and vascular biology: implications in human hypertension

Increased vascular production of reactive oxygen species (ROS; termed oxidative stress) has been implicated in various chronic diseases, including hypertension. Oxidative stress is both a cause and a consequence of hypertension. Although oxidative injury may not be the sole etiology, it amplifies blood pressure elevation in the presence of other pro-hypertensive factors. Oxidative stress is a multisystem phenomenon in hypertension and involves the heart, kidneys, nervous system, vessels and possibly the immune system. Compelling experimental and clinical evidence indicates the importance of the vasculature in the pathophysiology of hypertension and as such much emphasis has been placed on the (patho)biology of ROS in the vascular system. A major source for cardiovascular, renal and neural ROS is a family of non-phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), including the prototypic Nox2 homolog-based NADPH oxidase, as well as other Noxes, such as Nox1 and Nox4. Nox-derived ROS is important in regulating endothelial function and vascular tone. Oxidative stress is implicated in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, fibrosis, angiogenesis and rarefaction, important processes involved in vascular remodeling in hypertension. Despite a plethora of data implicating oxidative stress as a causative factor in experimental hypertension, findings in human hypertension are less conclusive. This review highlights the importance of ROS in vascular biology and focuses on the potential role of oxidative stress in human hypertension.

Vascular Remodeling in Hypertension and Metabolic Syndrome

Vascular Remodeling in Hypertension and Metabolic Syndrome

Effects of lignans extracted from Eucommia ulmoides and aldose reductase inhibitor epalrestat on hypertensive vascular remodeling

To investigate the effects of lignans extracted from Eucommia ulmoides and epalrestat on vascular remodeling in spontaneously hypertensive rats. Ten-week-old male spontaneously hypertensive rats were randomly divided into 3 groups (12 rats each group), and treated orally with 100 mg/kg/d of captopril (an angiotensin-converting enzyme inhibitor), 100 mg/kg/d of epalrestat (an aldose reductase inhibitor) and 300 mg/kg/d of lignans by gavage daily for 16 weeks, respectively. Sex-, age-, and number-matched spontaneously hypertensive rats and normotensive Wistar Kyoto rats, were treated with distilled water (vehicle) as controls. The rats were weighed weekly. Mean arterial blood pressure and heart rate were measured periodically by non-invasive blood pressure monitoring. They were sacrificed at the end of experiment (26-week-old). Superior mesenteric artery and aorta were isolated for determination of histomorphometry and the expression of aldose reductase by immunohistochemistry. Captopril and lignans, but not epalrestat, decreased mean arterial blood pressure in spontaneously hypertensive rats. Vascular remodeling was improved in all three treated groups by histomorphometry. Both lignans and epalrestat reversed hypertensive vascular remodeling. Aldose reductase played a vital role in the pathologic process of hypertensive vascular remodeling rather than elevation of blood pressure. These data suggested that aldose reductase could be a new therapeutic target for the treatment of cardiovascular diseases.

Dynamic expression of proteins associated with adventitial remodeling in adventitial fibroblasts from spontaneously hypertensive rats

To identify proteins that could potentially be involved in adventitial remodeling in vascular adventitial fibroblasts (AFs) from spontaneously hypertensive rats (SHR). AFs were isolated from thoracic aortas of 4-, 8-, 16-, and 24-week-old male SHR and Wistar-Kyoto (WKY) rats and cultured to passage 4. Proteomic differential expression profiles between SHR-AFs and WKY-AFs were investigated using 2-D electrophoresis (2-DE), whereas gel image analysis was processed using Image Master 2D Platinum. Protein spots were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Expression levels of annexin A1 in AFs and aortas from SHR and WKY rats were detected with Western blotting and immunofluorescence techniques. In 4-, 8-, 16-, and 24-week-old SHR-AFs, 49, 59, 54, and 69 protein spots were found to have significant differences from the age-matched WKY-AFs. Fourteen spots with the same changes in patterns were analyzed in 4-, 8-, 16-, and 24-week-old SHR-AFs with mass spectrometry. Except for cytoskeleton proteins such as tubulin beta 5, it was found that annexin A1, translation elongation factor Tu, endoplasmic reticulum protein 29 and calcium-binding protein 1 were expressed in vascular AFs and their levels changed significantly in SHR-AFs compared with those in WKY-AFs. A decrease in annexin A1 in SHR-AFs was confirmed with Western blotting and immunofluorescence staining at the cell and tissue levels. The application of proteomic techniques revealed a number of novel proteins involved in adventitial remodeling of AFs from SHR, which provide new mechanisms responsible for the occurrence and development of hypertension and potential targets for influencing vascular remodeling in hypertension.

Calcium antagonists, diltiazem and nifedipine, protect broilers against low temperature‐induced pulmonary hypertension and pulmonary vascular remodeling

This study was designed to determine whether calcium antagonists, diltiazem and nifedipine, can depress low temperature-induced pulmonary hypertension (PH) in broilers (also known as ascites) and to characterize their efficacy on hemodynamics and pulmonary artery function. Chicks were randomly allocated into six experimental groups and orally administered with vehicle, 5.0 mg/kg body weight (BW)/12 h nifedipine or 15.0 mg/kg BW/12 h diltiazem from 16 to 43 days of age under low temperature. The mean pulmonary arterial pressure (mPAP), the ascites heart index (AHI), the erythrocyte packed cell volume (PCV) and the relative percentage of medial pulmonary artery thickness were examined on days 29, 36 and 43. The data showed that administration of diltiazem protected broilers from low temperature-induced pulmonary hypertension and vascular remodeling. Although nifedipine prevented mPAP from increasing during the early stage, it did not suppress the development of PH during the late stage and did not keep heart rate (HR), PCV, AHI and the thickness of pulmonary small artery smooth muscle layer at the normal levels. Taken together, our results showed that diltiazem can effectively prevent low temperature-induced pulmonary hypertension in broilers with fewer side-effects and may be a potential compound for the prevention of this disease in poultry industry.

Tensorial Description of the geometrical arrangement of Endothelin‐1 in response to the changes of blood pressure in rat's aorta

For better studying the vascular remodeling in hypertension, the geometrical arrangement of the cellular molecules, which are the foundation of the physical behavior of the cells and tissues, has to be described quantitatively. Endothelin‐1 (ET‐1) is a vasoconstrictor and mitogenic agent, and has been found in the vascular endothelium, the vascular smooth muscle cells, and the fibroblasts. This study aimed to investigate quantitatively the changes of the geometrical distribution of ET‐1 in blood vessel wall in response to the changes of blood pressure. By clamping one cross section of the rat's abdominal aorta, the blood pressure in the aorta was raised in the portion above the clamp, and lowered in the portion below the clamp. The effects of the raising or the lowering of the blood pressure on these two portions of the aorta simultaneously on the tissue remodeling in the abdominal aortas were studied after aortic banding for 0, 0.5, 4, or 8 days. Aortic cross sections in circumferential and longitudinal directions and En Face were prepared and immunostained with ET‐1 antibody for examination by a fluorescent microscope. Digital images were taken for analysis. The geometrical distributions of ET‐1 in the vessel wall was described by a Molecular configuration tensor, Pij, where the subscripts i, j refer to the Cartesian coordinate axes x1, x2, x3. All components in the molecular configuration tensor of ET‐1 are presented.

Kinetics of cardiac and vascular remodeling by spontaneously hypertensive rats after discontinuation of long-term captopril treatment

Angiotensin-converting enzyme inhibitors reduce blood pressure and attenuate cardiac and vascular remodeling in hypertension. However, the kinetics of remodeling after discontinuation of the long-term use of these drugs are unknown. Our objective was to investigate the temporal changes occurring in blood pressure and vascular structure of spontaneously hypertensive rats (SHR). Captopril treatment was started in the pre-hypertensive state. Rats (4 weeks) were assigned to three groups: SHR-Cap (N = 51) treated with captopril (1 g/L) in drinking water from the 4th to the 14th week; SHR-C (N = 48) untreated SHR; Wistar (N = 47) control rats. Subgroups of animals were studied at 2, 4, and 8 weeks after discontinuation of captopril. Direct blood pressure was recorded in freely moving animals after femoral artery catheterism. The animals were then killed to determine left ventricular hypertrophy (LVH) and the aorta fixed at the same pressure measured in vivo. Captopril prevented hypertension (105 + or - 3 vs 136 + or - 5 mmHg), LVH (2.17 + or - 0.05 vs 2.97 + or - 0.14 mg/g body weight) and the increase in cross-sectional area to luminal area ratio of the aorta (0.21 + or - 0.01 vs 0.26 + or - 0.02 microm(2)) (SHR-Cap vs SHR-C). However, these parameters increased progressively after discontinuation of captopril (22nd week: 141 + or - 2 mmHg, 2.50 + or - 0.06 mg/g, 0.27 + or - 0.02 microm(2)). Prevention of the development of hypertension in SHR by using captopril during the prehypertensive period prevents the development of cardiac and vascular remodeling. Recovery of these processes follows the kinetic of hypertension development after discontinuation of captopril.

Superoxide enhances cell proliferation in pulmonary artery adventitial fibroblasts from chronically hypoxic calves and augments expression of the redox‐sensitive transcription factor, Egr‐1

Superoxide (O2−) has been implicated in chronic hypoxia‐induced pulmonary hypertension (CHPH) and pulmonary vascular remodeling. In a calf model of CHPH, the pulmonary artery adventitial fibroblast (PAAF) proliferates in vivo and in vitro and contributes to vascular remodeling. Hypoxia‐induced proliferation of PAAF is mediated in part by a redox‐sensitive transcription factor, early growth response‐1 (Egr‐1). We hypothesized that ROS are responsible for the proliferation observed in PAAF from the chronically hypoxic (HA) calf through Egr‐1. We cultured PAAF isolated from HA neonatal calves in the presence or absence of the antioxidant, superoxide dismutase (SOD, 200 U/ml) for up to 6 days and measured changes in cell counts by hemocytometer and MTT assay. We exposed cells to xanthine and xanthine oxidase (8 mU/mL) to generate O2−, and measured Egr‐1 mRNA expression by real‐time PCR. We found that SOD decreased proliferation in PAAF from HA calves. Treatment of HA PAAF with xanthine/xanthine oxidase increased Egr‐1 mRNA expression by 2 fold (p&lt;0.05 by unpaired t‐test). These data provide evidence that O2− contributes to the proliferation of PAAF from HA calves and support the hypothesis that O2− may regulate cell proliferation by upregulating the transcription factor, Egr‐1.

Role of extracellular matrix in vascular remodeling of hypertension

Arterial stiffness due to alterations in extracellular matrix is one of the mechanisms responsible for increased peripheral resistance in hypertension. Recent evidence points to arterial stiffness as an independent predictor of cardiovascular events. This review focuses on recent advances in the biology of extracellular matrix proteins involved in hypertension-associated vascular changes. The vascular extracellular matrix is a complex heterogeneous tissue comprising collagens, elastin, glycoproteins, and proteoglycans. These constituents not only provide mechanical integrity to the vessel wall but also possess a repertoire of insoluble ligands that induce cell signaling to control proliferation, migration, differentiation, and survival. It is now evident that it is not only the quantity but also the quality of the new synthesized extracellular matrix that determines changes in vascular stiffness in hypertension. Also, the control of cross-linking and the interactions between the extracellular matrix and vascular cells seem to be important. It is now evident that some of the currently used antihypertensive therapies can correct vascular stiffness and fibrosis. A better understanding of molecular mechanisms underlying alterations in extracellular matrix in hypertension will provide insights into novel therapies to reduce arterial stiffness and will identify new roles of established antihypertensive drugs.