Vascular Structural Remodeling Research Articles

Chronic administration of adrenomedullin attenuates hypoxic pulmonary vascular structural remodeling and inhibits proadrenomedullin N-terminal 20-peptide production in rats

Adrenomedullin (ADM) is a novel cardiovascular-active peptide involved in vasodilation, reducing blood pressure and inhibiting vascular smooth muscle cell migration and proliferation. Previous research showed that ADM might be involved in the development of pulmonary hypertension. In this study, we investigated the effect of ADM subcutaneously administered by mini-osmotic pump (300 ng/h) on pulmonary hemodynamics and pulmonary vascular structure in hypoxic rats, as well as the influence of ADM on the proadrenomedullin N-terminal 20-peptide (PAMP) protein and mRNA expressions and its plasma concentrations. The results showed that ADM obviously decreased mean pulmonary artery pressure and the ratio of right ventricular mass to left ventricular plus septal mass in hypoxic rats. Chronic infusion of ADM lessened the muscularization of small pulmonary vessels, attenuated relative medial thickness and relative medial area of pulmonary arteries, and alleviated the ultrastructural changes in pulmonary arteries of hypoxic rats. ADM inhibited the proliferation of pulmonary artery smooth muscle cells, represented by a decrease in the expression of proliferative cell nuclear antigen (PCNA) in the pulmonary artery. Meanwhile, plasma PAMP concentration and the expression of PAMP protein and mRNA by pulmonary arteries in rats of hypoxia with ADM group were markedly decreased compared with those in hypoxic group. The results suggest that ADM ameliorated the development of hypoxic pulmonary vascular structural remodeling. Intramolecular regulation of ADM may play an important role in the regulation of hypoxic pulmonary hypertension by ADM.

Mechanism by which hydrogen sulfide regulates pulmonary vascular structural remodeling induced by high pulmonary blood flow in rats

Pulmonary hypertension (PH) is a common complication of congenital heart defects with a left-to-right shunt characterized by high pulmonary blood flow. Pulmonary vascular structural remodeling (PVSR) is the pathological basis of PH. However, the pathophysiologic features and mechanisms responsible for PH and PVSR induced by increased pulmonary blood flow have not been fully understood. The present study was designed to explore the possible effect and mechanism of hydrogen sulfide (H(2)S) on the regulation of PVSR induced by high pulmonary flow in rats. Thirty-two male SD rats, weighing 120 - 140 g, were randomly divided into shunt group (n = 8), shunt + NaHS group (n = 8), control group (n = 8) and control + NaHS group (n = 8). Rats in shunt group and shunt + NaHS group were subjected to an abdominal aorta-inferior vena cava shunt to create an animal model of high pulmonary flow. Rats in the control and control + NaHS groups underwent the same experimental protocol as mentioned above except for the shunt procedure. Rats in the shunt + NaHS and control + NaHS groups were intraperitoneally injected with NaHS at 56 micromol/(kgxd), and rats in the shunt and control groups were injected with the same volume of physiological saline. After 11 weeks of experiment, rats were sacrificed and lung tissues were obtained. The percentage of muscularized artery (MA) was calculated. The changes in relative medial thickness (RMT) in small pulmonary arteries and median pulmonary arteries were examined. Proliferative cell nuclear antigen (PCNA), extracellular signal-regulated kinase (ERK1) and phosphorylation extracellular signal-regulated kinase (P-ERK1) protein expression were examined by Western blot, and at the same time, PCNA protein expression by pulmonary artery smooth muscle cells was observed by immunohistochemistry. After 11 weeks of shunt, compared with control group, the percentage of MA increased significantly (25.12 +/- 2.26 vs 14.42 +/- 3.41, P < 0.05), and RMT in small pulmonary arteries and median pulmonary arteries increased significantly in rats of shunt group (23.6 +/- 3.5 vs 12.6 +/- 2.1, 24.8 +/- 1.9 vs 13.5 +/- 2.2, P < 0.05 for all). PCNA protein expression in small and median pulmonary arteries increased significantly (0.49 +/- 0.04 vs 0.39 +/- 0.07, 0.46 +/- 0.08 vs 0.36 +/- 0.05, P < 0.01 for all), and the ratio of PERK/ERK1 protein expression of pulmonary arteries increased significantly (P < 0.01) in rats of shunt group compared with those of control group. After the administration of exogenous H(2)S donor, NaHS, for 11 weeks, in contrast to rats in shunt group, the percentage of MA decreased significantly (21.5 +/- 2.0 vs 25.1 +/- 2.3, P < 0.05), and RMT in small and median pulmonary arteries decreased significantly (20.2 +/- 2.8 vs 23.6 +/- 3.5, 20.8 +/- 3.1 vs 20.8 +/- 3.1, P < 0.05 for all) in rats of shunt + NaHS group. PCNA protein expression in small and median pulmonary artery smooth muscle cells decreased significantly (0.32 +/- 0.06 vs 0.49 +/- 0.04, 0.29 +/- 0.07 vs 0.46 +/- 0.08, P < 0.01 for all), and the ratio of PERK/ERK1 protein expression of pulmonary arteries decreased significantly (P < 0.01) in rats of shunt + NaHS group compared with that of shunt group. H(2)S may play a regulatory role in pulmonary vascular structural remodeling induced by high pulmonary blood flow via mitogen-activated protein kinase (MAPK)/ERK signal transduction pathway.

Induction of matrix metalloproteinase-2 enhances systemic arterial contraction after hypoxia

This study was carried out to determine the role of increased vascular matrix metalloproteinase-2 (MMP-2) expression in the changes in systemic arterial contraction after prolonged hypoxia. Rats and mice were exposed to hypoxia (10% and 8% O(2), respectively) or normoxia (21% O(2)) for 16 h, 48 h, or 7 days. Aortae and mesenteric arteries were either mounted in organ bath myographs or frozen in liquid nitrogen. MMP-2 inhibition with cyclic CTTHWGFTLC (CTT) reduced contraction to phenylephrine (PE) in aortae and mesenteric arteries from rats exposed to hypoxia for 7 days but not in vessels from normoxic rats. Similarly, CTT reduced contraction to Big endothelin-1 (Big ET-1) in aortae from rats exposed to hypoxia for 7 days. Responses to PE were reduced in hypoxic MMP-2(-/-) mice compared with MMP-2(+/+) mice. Increased contraction to Big ET-1 after hypoxia was observed in MMP-2(+/+) mice but not in MMP-2(-/-) mice. Rat aortic MMP-2 and membrane type 1 (MT1)-MMP protein levels and MMP activity were increased after 7 days of hypoxia. Rat aortic MMP-2 and MT1-MMP mRNA levels were increased in the deep medial vascular smooth muscle. We conclude that hypoxic induction of MMP-2 expression potentiates contraction in systemic conduit and resistance arteries. This may preserve the capacity to regulate the systemic circulation in the transition between the alterations in vascular tone and structural remodeling that occurs during prolonged hypoxic epochs.

MDM2: A Novel Mineralocorticoid-Responsive Gene Involved in Aldosterone-Induced Human Vascular Structural Remodeling

Aldosterone has been demonstrated to play an important role in the pathogenesis of various cardiovascular diseases. Vascular structural remodeling, including vascular smooth muscle cell (VSMC) proliferation, has been also reported in small resistance arteries of patients with primary aldosteronism. Therefore, in this study, we examined whether genes involved in the regulation of the cell cycle were induced by aldosterone alone in cultured human VSMCs and in human small resistance arteries. Results of these studies eventually demonstrated that MDM2, one of the genes involved in anti-apoptosis and cell growth, was markedly increased in mineralocorticoid receptor (MR)-positive VSMCs by aldosterone in all microarray, reverse transcriptase-polymerase chain reaction, immunoblotting, and immunofluorescence analyses. In addition, an analysis using small interfering RNA demonstrated that this gene product was involved in cell proliferation of VSMCs induced by aldosterone. Eplerenone, a specific MR antagonist, inhibited this gene induction by aldosterone in VSMCs. MDM2 protein was also more abundant in VSMCs of small resistance arteries in patients with primary aldosteronism compared with a control population. MDM2 is therefore considered one of the mineralocorticoid-responsive genes that regulates cell proliferation of VSMCs induced by MR-mediated aldosterone stimulation, possibly playing an important role in aldosterone-induced vascular structural remodeling.

Sodium hydrosulfide alleviated pulmonary vascular structural remodeling induced by high pulmonary blood flow in rats1

To explore the possible role of endogenous hydrogen sulfide (H(2)S), a novel gasotransmitter, in the pathogenesis of pulmonary vascular structural remodeling (PVSR) induced by high pulmonary blood flow. Thirty-two Sprague-Dawley male rats were randomly divided into sham, shunt, sham+NaHS (a H(2)S donor) and shunt+NaHS groups. Rats in shunt and shunt+NaHS groups underwent an abdominal aorta-inferior vena cava shunt, and rats in shunt+NaHS and sham+NaHS groups were intraperitoneally injected with NaHS. PVSR was investigated using optical microscope and transmission electron microscope. Lung tissue H(2)S was evaluated by sulfide-sensitive electrodes. Nitric oxide synthase (NOS), heme oxygenase (HO-1), proliferative cell nuclear antigen (PCNA) and extracellular signal-regulated kinase (ERK) activation were analyzed by Western blotting. After 11 weeks of shunting, PVSR developed with a decrease in lung tissue H(2)S production and an increase in nitric oxide (NO). However, lung tissue carbon monoxide (CO) did not change. After the treatment with NaHS for 11 weeks, H(2)S donor ameliorated PVSR and downregulated PCNA expression and ERK activation with an increase in lung tissue CO production and HO-1 protein expression but a decrease in NO production, NOS activity and eNOS protein expression in shunted rats. H(2)S exerted a regulatory effect on PVSR induced by high pulmonary blood flow. Meanwhile, H(2)S down-regulated the ERK/MAPK signal pathway, inhibited the NO/NOS pathway and enhanced the CO/HO pathway in rats with high pulmonary blood flow.

Functional and Structural Vascular Remodeling in Elite Rowers Assessed by Cardiovascular Magnetic Resonance

We aimed to noninvasively quantify the effects of chronic exercise training on both peripheral and central conduit artery function and structure with high-resolution magnetic resonance imaging (MRI). Physical activity has well-known beneficial effects on vascular function in subjects with endothelial dysfunction. Exercise also leads to beneficial effects on endothelial function in elderly athletes, possibly contributing toward the reduced risk from coronary artery disease in this age group. However, conflicting data exist on the training effects in the younger population. A total of 49 young (age 20 to 35 years) nonsmoking subjects, comprising elite rowers and age- and gender-matched sedentary control subjects, underwent MRI (1.5-T). The ascending, the proximal descending, and the distal descending aorta, and the common carotid artery and the brachial artery were assessed for diastolic and systolic area and distensibility. Endothelial-dependent and -independent brachial artery dilatation were also assessed by cine MRI. Rowers showed vascular remodeling with enlarged brachial (by 51%, p < 0.001) and reduced central conduit artery cross-sectional areas (by up to 28% [e.g., distal descending aorta], p < 0.001). Vessel distensibilities (mm Hg(-1)) were similar for elite rowers when compared with sedentary control subjects at all levels of the aorta and the carotid and brachial artery (p > 0.05 for all). Endothelial-dependent dilation (percentage and mm2) was similar for rowers and control subjects (p > 0.05). However, rowers showed reduced absolute (by 33%) endothelial-independent dilation (p < 0.001). Young elite rowers demonstrate normal endothelial-dependent but reduced endothelial-independent dilation. Chronic, whole body, combined endurance- and strength-training does not lead to changes in arterial stiffness but to vascular remodeling.

Experimental Study of Effect of Fontan Circuit on Pulmonary Microcirculation

Pulsatile pulmonary blood flow plays an important role in regulating shear-stress-mediated release of endothelium-derived nitric oxide and endothelin-1, and it reduces pulmonary vascular resistance by passive capillary recruitment. The aim of this study was to demonstrate changes in pulmonary capillary structure and endothelial function induced by the chronic nonpulsatile flow of the Fontan circulation. A canine model with nonpulsatile flow in the right lung was established, and sacrificed 3 months later. Compared to the left lung, wall thickness of the pulmonary arterioles was thinner, endothelin-1 expression was weaker, endothelial nitric oxide synthase activity was stronger, and there was a good correlation between the histomorphometric and immunohistochemical findings. These data indicate that long-term nonpulsatile flow can lead to endothelial dysfunction, which may be involved in distention and vascular structure remodeling due to the increase in pulmonary vascular resistance; but it also can lead to increased patency of the arteriovenous shunt, which might be at least partly involved in pulmonary arteriovenous fistula development and exercise limitation after the Fontan operation.

Inhalation of nebulized nitroglycerin, a nitric oxide donor, for the treatment of pulmonary hypertension induced by high pulmonary blood flow

This study explores the effect and mechanisms of inhalation of nebulized nitroglycerin (Neb-NTG) on pulmonary hypertension induced by high pulmonary blood flow. An aortocaval shunt was produced in rats. Twelve weeks after the operation, rats started to inhale Neb-NTG. After 15 weeks, pulmonary and systemic hemodynamics as well as pathological changes were measured in all animals. Inhalation of Neb-NTG was able not only to markedly attenuate pulmonary artery pressure without impacting systolic pressure but also to ameliorate muscularization of small pulmonary arteries. The relaxation response of pulmonary artery ring to acetylcholine in shunt rats and Neb-NTG-treated rats was decreased. However, Neb-NTG did not impact the relaxation response of pulmonary artery ring to both nitroprusside and nitroglycerin (NTG). Neb-NTG successfully inhibited the increased expression of pulmonary artery smooth muscle cell (PASMC) proliferative cell nuclear antigen, collagen I, and collagen III, as well as pulmonary artery urotensin-II in shunt rats with high pulmonary blood flow. Neb-NTG selectively ameliorated pulmonary hypertension as well as pulmonary vascular structural remodeling induced by high pulmonary blood flow.

Impact of l-arginine on hydrogen sulfide/cystathionine-γ-lyase pathway in rats with high blood flow-induced pulmonary hypertension

The present study was designed to explore the possible effect of l-arginine on endogenous hydrogen sulfide/cystathionine-γ-lyase (H 2S/CSE) pathway in the pathogenesis of pulmonary hypertension and pulmonary vascular structural remodeling induced by high pulmonary blood flow. Thirty-two male Sprague–Dawley rats were randomly divided into control group ( n = 11), shunt group ( n = 11) and shunt with l-arginine group ( n = 10). Rats in the shunt and shunt with l-arginine group underwent an abdominal aorta-inferior cava vein shunt operation. After 11 weeks of shunting, the plasma level of H 2S and lung tissue H 2S production rate in the shunt with l-arginine group were much higher than those in the shunt group ( P < 0.01). Meanwhile, the expression of CSE mRNA in the lung tissues of rats in the shunt with l-arginine group was increased significantly ( P < 0.01), and in situ hybridization showed that CSE mRNA expression was obviously up-regulated in the smooth muscle cells (SMCs) of the pulmonary arteries of shunted rats treated with l-arginine when compared with shunted rats without the treatment of l-arginine ( P < 0.01). In conclusion, H 2S/CSE pathway was up-regulated by l-arginine in pulmonary hypertension induced by high blood flow with the attenuation of pulmonary hypertension and pulmonary vascular structural remodeling.

A Newly Found Gasotransmitter, Hydrogen Sulfide, in the Pathogenesis of Hypertension and Other Cardiovascular Diseases

In the 1980s, nitric oxide (NO) and carbon monoxide (CO) were determined to be gaseous messenger molecules which is capable of relaxing vessels and interfering with vascular structure remodeling. However there are many mechanisms that have not been clear about the regulation of human functions under both physiological and pathophysiological conditions. Hydrogen sulfide (H2S) is a newly found gasotrasmitter that was demonstrated to play similar role as that of NO and CO in many organs and tissues, especially in the cardiovascular system. In this review, firstly, we described the production of H2S in the body, and the functions of H2S in the cardiovascular system, especially in the vascular relaxing and vascular remodeling. Secondly, we further discussed the role of H2S in hypertension, hypoxic pulmonary hypertension, shock and ischemic hear disease. Finally, the interaction between H2S and the other two gasotransmitters, NO and CO, was also discussed. Keywords: Hydrogen sulfide, cardiovascular system, hypertension, pulmonary hypertension

Recipient-Derived Cells in the Tissue Repair of Renal Allografts

To observe the roles of recipient-derived cells in renal allografts with acute cellular rejection (ACR), eight male patients who had received a female donor kidney were enrolled, with protocol renal allograft biopsies. Three of them suffered from ACR, and the other five with normal function. Biopsy sections were detected for the presence of recipient-derived cells and their phenotypes. Recipient-derived cells appeared in the tubular epithelium as early as 13 days posttransplant, with the phenotype of cytokeratin(+)/CD45(-). They also localized in the medium walls of arterioles and expressed alpha-SMA. In patients with ACR, recipient-derived tubular cells increased persistently during the first 6 months (3.8 to 6.6%). Long-term follow up showed a decline in their number when ACR ameliorated. In patients without ACR, the infiltration rate remained stable (0.6-2.3%). Recipient-derived cells participate the remodeling of renal allografts. They might have a close relationship with ACR outcome and with vascular structure remodeling.

Effect of L-Arginine on Pulmonary Artery Smooth Muscle Cell Apoptosis in Rats with Hypoxic Pulmonary Vascular Structural Remodeling

This study investigated the effect of L-arginine (L-Arg) on the apoptosis of pulmonary artery smooth muscle cells (PASMC) in rats with hypoxic pulmonary vascular structural remodeling, and its mechanisms. Seventeen Wistar rats were randomly divided into a control group (n=5), a hypoxia group (n=7), and a hypoxia+L-Arg group (n=5). The morphologic changes of lung tissues were observed under optical microscope. Using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay, the apoptosis of PASMC was examined. Fas expression in PASMC was examined using immunohistochemistry. The results showed that the percentage of muscularized artery in small pulmonary vessels, and the relative medial thickness and relative medial area of the small and median pulmonary muscularized arteries in the hypoxic group were all significantly increased. Pulmonary vascular structural remodeling developed after hypoxia. Apoptotic smooth muscle cells of the small and median pulmonary arteries in the hypoxia group were significantly less than those in the control group. After 14 d of hypoxia, Fas expression by smooth muscle cells of median and small pulmonary arteries was significantly inhibited. L-Arg significantly inhibited hypoxic pulmonary vascular structural remodeling in association with an augmentation of apoptosis of smooth muscle cells as well as Fas expression in PASMC. These results showed that L-Arg could play an important role in attenuating hypoxic pulmonary vascular structural remodeling by upregulating Fas expression in PASMC, thus promoting the apoptosis of PASMC.

Effects of hydrogen sulfide on hypoxic pulmonary vascular structural remodeling

To study the role of hydrogen sulfide (H 2S) in hypoxic pulmonary vascular structural remodeling (HPVSR), a total of 24 Wistar rats were randomly divided into three groups: control group ( n = 8), hypoxia group ( n = 8) and hypoxia with sodium hydrosulfide (hy + NaHS) group ( n = 8). The mean pulmonary artery pressure (mPAP), plasma H 2S and the percentage of muscularized arteries (MA), partially muscularized arteries (PMA) and nonmuscularized arteries (NMA) in small pulmonary vessels were measured. Collagen I and III, elastin, transforming growth factor-β 3 (TGF-β 3), proliferative cell nuclear antigen (PCNA) and human urotensin II(U-II) expressions were detected by immunohistochemical assay. The mRNA expressions of procollagen I and III, matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinease-1 (TIMP-1) were detected by in situ hybridization. The results showed that NaHS significantly increased plasma H 2S, decreased mPAP and the percentage of MA and PMA of small pulmonary vessels in rats under hypoxia. Meanwhile, NaHS inhibited the proliferation of pulmonary artery smooth muscle cells (PASMCs) represented by a decrease in the expressions of PCNA and human U-II in pulmonary artery wall. NaHS reduced the expression of collagen I and III, elastin and TGF-β 3 protein and decreased the expressions of procollagen I and III mRNA in pulmonary arteries of rats under hypoxia, but it did not impact the ratio of TIMP-1 mRNA to MMP-1mRNA in pulmonary arteries of rats under hypoxia. These data suggested that H 2S played an important role in the development of HPVSR.

Reactive Oxygen Species as Mediators of Calcium Signaling by Angiotensin II: Implications in Vascular Physiology and Pathophysiology

Reactive oxygen species (ROS), including superoxide anion, hydrogen peroxide, and hydroxyl radical, and reactive nitrogen species, such as nitric oxide and peroxynitrite, are biologically relevant O2 derivatives increasingly being recognized as important in vascular biology through their oxidation/reduction (redox) potential. All vascular cell types produce ROS primarily via membrane-associated NAD(P)H oxidase. ROS influence vascular function by modulating contraction/dilation, cell growth, apoptosis/anoikis, migration, inflammation, and fibrosis. An imbalance in redox state where prooxidants overwhelm antioxidant capacity results in oxidative stress. Oxidative excess and associated oxidative damage are mediators of altered vascular tone and structural remodeling in many cardiovascular diseases. ROS elicit these effects by influencing intracellular signaling events. In addition to modulating protein tyrosine kinases, protein phosphatases, mitogen-activated protein kinases, and transcription factors, ROS are important regulators of intracellular Ca2+ homeostasis and RhoA/Rho kinase signaling. ROS increase vascular [Ca2+]i by stimulating inositol trisphosphate-mediated Ca2+ mobilization, by increasing cytosolic Ca2+ accumulation through sarcoplasmic/endoplasmic reticulum Ca2+-ATPase inhibition, and by stimulating Ca2+ influx through Ca2+ channels. Increased ROS generation enhances Ca2+ signaling and up-regulates RhoA/Rho kinase, thereby altering vascular contractility and tone. The present review discusses the importance of ROS in angiotensin II signaling in vascular biology and focuses specifically on the role of oxidative stress in Ca2+ signaling in the vasculature.

Inhaled Iloprost Reverses Vascular Remodeling in Chronic Experimental Pulmonary Hypertension

Inhaled iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled iloprost on changes to pulmonary vascular structure that occur in PAH. The present study was designed to investigate chronic antiremodeling effects of inhaled iloprost in monocrotaline (MCT)-induced PAH in rats. Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with iloprost at a dose of 6 microg . kg(-1) . day(-1), or underwent sham nebulization with saline. After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to iloprost. Furthermore, the MCT-induced increase in matrix metalloproteinase-2 and -9 activities and tenascin-C expression was suppressed. We conclude that the inhalation of iloprost reverses PAH and vascular structural remodeling in MCT-treated rats. This regimen suggests the possibility of an antiremodeling therapy in PAH.

Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension

Pulmonary hypertension is a fatal disease characterized by vasoconstriction and vascular remodeling. Loss of endothelial nitric oxide bioavailability is implicated in pulmonary hypertension pathogenesis. Recent evidence suggests that the cofactor tetrahydrobiopterin (BH4) is an important regulator of nitric oxide synthase enzymatic function. In the hph-1 mouse with deficient BH4 biosynthesis, BH4 deficiency caused pulmonary hypertension, even in normoxic conditions, and greatly increased susceptibility to hypoxia-induced pulmonary hypertension. In contrast, augmented BH4 synthesis in the endothelium, by targeted transgenic overexpression of GTP-cyclohydrolase I (GCH), prevented hypoxia-induced pulmonary hypertension. Furthermore, specific augmentation of endothelial BH4 in hph-1 mice by crossing with GCH transgenic mice rescued pulmonary hypertension induced by systemic BH4 deficiency. Lung BH4 availability controlled pulmonary vascular tone, right ventricular hypertrophy, and vascular structural remodeling in a dose-dependent manner in both normoxia and hypoxia. Furthermore, BH4 availability had striking effects on the immediate vasoconstriction response to acute hypoxia. These effects of BH4 were mediated through the regulation of nitric oxide compared with superoxide synthesis by endothelial nitric oxide synthase. Endothelial BH4 availability is essential for maintaining pulmonary vascular homeostasis, is a critical mediator in the pathogenesis of pulmonary hypertension, and is a novel therapeutic target.

Down-Regulation of Endogenous Hydrogen Sulfide Pathway in Pulmonary Hypertension and Pulmonary Vascular Structural Remodeling Induced by High Pulmonary Blood Flow in Rats

The mechanisms responsible for the development of pulmonary hypertension (PH) and pulmonary vascular structural remodeling induced by high pulmonary blood flow are not fully understood. The present study was designed to explore the possible changes in endogenous hydrogen sulfide (H2S), a novel gasotransmitter, on the pathogenesis of PH and pulmonary vascular structural remodeling induced by high pulmonary blood flow. Twenty-two male Sprague-Dawley rats were randomly divided into a shunting group (n=11) and control group (n=11). Rats in the shunting group underwent an abdominal aorta-inferior cava vein shunting operation. After 11 weeks of shunting, the plasma level of H2S and lung tissue H2S producing rate were much lower than those of the control group (p<0.01). In situ hybridization analysis showed that the expression of cystathionine gamma-lyase (CSE) mRNA was down-regulated in the pulmonary arteries of the shunting rats compared with the control group (p<0.01), and competitive quantitative reverse transcription-polymerase chain reaction showed that the relative amount of CSEmRNA in lung tissue was decreased significantly (p<0.01). The endogenous H2S pathway is down-regulated in PH and pulmonary vascular structural remodeling is induced by high pulmonary blood flow.

Effect of L-Arginine on Collagen of High Flow-Induced Pulmonary Arterial Remodeling

Pulmonary hypertension (PH) is a common complication of congenital heart disease and pulmonary vascular structural remodeling due to the high pulmonary blood flow is considered as the key pathologic process. In the present study the effects of L-arginine on the collagen metabolism of pulmonary arteries in rats with high pulmonary blood flow-induced PH were investigated to elucidate its mechanism. The rat model of PH was established with an abdominal aorta and inferior vena cava shunt. L-arginine (1 g/kg per day) was given directly into the stomachs of the rats with the shunt (L-arginine+shunt group) and 11 weeks later, the pulmonary hemodynamics were studied. Collagen I and collagen III expressions were detected by immunohistochemical assay. The expressions of procollagen I mRNA, procollagen III mRNA, the tissue inhibitor of metalloproteinase-1 mRNA and the matrix metalloproteinase-1 mRNA were detected by in situ hybridization. The expressions of pulmonary artery collagen I, collagen III, procollagen I mRNA and procollagen III mRNA in the shunt rats were obviously elevated compared with the control rats (p<0.01). The positive signals were mainly located in the media and adventitia of median and small pulmonary arteries. The expressions of the pulmonary artery tissue inhibitor of metalloproteinase-1 mRNA, metalloproteinase-1 mRNA and the ratio of tissue inhibitor of metalloproteinase-1/metalloproteinase-1 were elevated in the shunt rats (p<0.01). However, the expressions of pulmonary artery collagen I, collagen III, procollagen I mRNA and procollagen III mRNA were significantly reduced in the shunt rats of the L-arginine group (p<0.01). L-arginine also downregulated the expressions of tissue inhibitor of metalloproteinase-1 mRNA and metalloproteinase-1 mRNA, as well as the ratio of tissue inhibitor of metalloproteinase-1/metalloproteinase-1 (p<0.05). L-arginine can reduce the synthesis of extracellular matrix-collagen and increase its degradation, thus having an important modulating effect on pulmonary vascular matrix remodeling induced by high pulmonary blood flow.

The upregulation of endothelial nitric oxide synthase and urotensin-II is associated with pulmonary hypertension and vascular diseases in rats produced by aortocaval shunting.

The mechanism of pulmonary vascular structural remodeling and pulmonary hypertension induced by high pulmonary blood flow is still unclear. Nitric oxide (NO) and carbon monoxide (CO) are two gaseous molecules recently discovered; both can induce the relaxation of blood vessels and inhibit the proliferation of vascular smooth muscle cells. More recently, urotensin-II (U-II) has been considered as the most potent mammalian vasoconstrictor identified so far, which can promote the proliferation of vascular smooth muscle cells. The aim of this study was to investigate the alteration of micro- and ultrapathologic structure, gaseous molecules, and U-II in rats with pulmonary hypertension induced by increased pulmonary blood flow. Aortocaval shunting was produced in rats. After 11-weeks of shunting, pulmonary artery mean pressure (PAMP) was measured. Pulmonary vascular micro- and ultrastructure was examined. Meanwhile, the concentration of plasma NO and CO was measured by spectrophotometry. The expression of endothelial nitric oxide synthase (eNOS), heme oxygenase-1 (HO-1), and U-II by pulmonary arteries was detected by immunohistochemistry. The results showed that PAMP was significantly elevated after 11 weeks of aortocaval shunting (2.99 +/- 0.35 kPa vs 2.09 +/- 0.38 kPa, P << 0.01). Muscularization of small pulmonary vessels and relative medial thickness of pulmonary arteries were obviously increased in shunt rats compared with controls. Ultrastructural changes were found in intrapulmonary arteries of shunt rats. Meanwhile, plasma NO concentration was increased and eNOS expression by pulmonary artery endothelial cells was significantly augmented in rats of the shunting group, but there was no significant difference in plasma CO level and HO-1 expression by pulmonary artery smooth muscle cells between shunting and sham groups. Urotensin-II expression by pulmonary artery endothelial cells and smooth muscle cells was significantly strengthened in shunt rats compared with sham rats. The results suggest that pulmonary vascular structural remodeling is an important pathologic basis of pulmonary hypertension induced by a left-to-right shunt. Upregulation of U-II might play an important role in the development of high pulmonary blood flow-induced pulmonary hypertension. Nitric oxide, as a modifying factor, might be involved in the regulation of pulmonary vascular structural remodeling.

Endothelial dysfunction in pulmonary hypertension.

The pathogenesis of pulmonary hypertension (PH) involves a complex and multifactorial process. Endothelial dysfunction seems to play an integral role in mediating the structural changes in the pulmonary vasculature. Disordered endothelial cell proliferation along with concurrent neoangiogenesis, when exuberant, results in the formation of glomeruloid structures known as the plexiform lesions, which are common pathological features of the pulmonary vessels of patients with pulmonary arterial hypertension (PAH). In addition, an altered production of various endothelial vasoactive mediators, such as NO, prostacyclin, endothelin-1 (ET-1), serotonin, and thromboxane, has been increasingly recognized in patients with PH. Because most of these mediators affect the growth of the smooth muscle cells, an alteration in their production may facilitate the development of pulmonary vascular hypertrophy and structural remodeling characteristic of PH. It is conceivable that the beneficial effects of many of the treatments currently available for PAH, such as the use of prostacyclin, NO, and ET antagonists, result at least in part from restoring the balance between these mediators. However, the ultimate cellular and physiological targets of these treatments remain unknown. In addition to the potential consequences of an imbalance in the endothelial production of various mediators, injury to the endothelium may expose the underlying vascular tissue to diverse blood-borne factors that may further promote pathological changes. Endothelial dysfunction may also have adverse consequences on pulmonary vascular hemostasis by altering the production of anticoagulant factors. Recent reports of genetic mutations in the endothelial cells of patients with PH further underscore the role of these cells in the disease pathogenesis. The endothelium lining the normal lung is characterized by significant heterogeneity. Not only is it vastly different from systemic endothelium in ultrastructure and function, but it varies in various vessel types in the pulmonary vasculature itself.1 The main functions of the pulmonary endothelium include maintenance …