Artery Remodeling In Rats Research Articles

Paradoxically reduced pulmonary vascular resistance and abnormal vascular remodeling in the obese spontaneously hypertensive heart failure ZSF1 rats

Pulmonary arterial dysfunction and remodeling often develop secondary to left heart disease and systemic hypertension. Excessive body weight is a well-established independent risk factor for the development of cardiovascular disease. However, data have emerged that for heart failure associated pulmonary complications obesity displays a lower long-term mortality. The impact of obesity on hypertension-related heart failure in affecting pulmonary vascular changes is incompletely understood. Here, we examined pulmonary vascular resistance and pulmonary artery function and remodeling in obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. 20-week-old male obese ZSF1 rats display increased left ventricle (LV) hypertrophy and diastolic dysfunction, when compared to age-matched lean spontaneously hypertensive heart failure (SHHR). Pulmonary vascular resistance, pulmonary arterial function and vascular wall remodeling were examined in isolated and perfused, ventilated lung preparations and isolated small pulmonary artery pressure and wire myography, respectively. We found that the pulmonary vascular resistance (normalized to lung weight) was significantly reduced in obese ZSF1 rats compared to SHHR (ZSF1: 0.2±0.02 mmHg·mL -1 ·min·g-1 vs SHHR: 0.29±0.018 mmHg·mL -1 ·min·g-1, p=0.01). In isolated pulmonary arteries the acetylcholine-induced relaxation was maintained, whereas the nitric oxide donor, sodium nitroprusside-induced relaxation was reduced in obese ZSF1 rats (SNP -log(IC50) ZSF1: 4.185±0.166 vs SHHR: 4.96±0.136, p=0.005). The wall thickness and wall-to-lumen ratio of pulmonary arteries were higher in the obese ZSF1 rats when compared to SHHR. Collectively, we found that obesity is associated with a reduced pulmonary vascular resistance and abnormal pulmonary artery remodeling in rats with systemic hypertension and diastolic heart failure, which may have implications in the clinically observed obesity paradox. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Transplantation of viable mitochondria improves right ventricular performance and pulmonary artery remodeling in rats with pulmonary arterial hypertension

ObjectiveBecause mitochondrial dysfunction is a key factor in the progression of pulmonary hypertension, this study tested the hypothesis that transplantation of exogenous viable mitochondria can reverse pulmonary artery remodeling and restore right ventricular performance in pulmonary hypertension. MethodsPulmonary hypertension was induced by parenteral injection of monocrotaline (60 mg/kg) and creation of a left-to-right shunt aortocaval fistula in rats. Three weeks after creation of fistula, the animals were randomly assigned to receive intravenous delivery of placebo solution or allogeneic mitochondria once weekly for 3 consecutive weeks. Mitochondria (100 μg) were isolated from the freshly harvested soleus muscles of naïve rats. Transthoracic echocardiography was performed at 3 weeks after mitochondrial delivery. ResultsEx vivo heart-lung block images acquired by an IVIS Spectrum (PerkinElmer, Waltham, Mass) imaging system confirmed the enhancement of MitoTracker (Invitrogen, Carlsbad, Calif) fluorescence in the pulmonary arteries. Mitochondria transplantation significantly increased lung tissue adenosine triphosphate concentrations and improved right ventricular performance, as evidenced by a reduction in serum levels of B-type natriuretic peptide and ventricular diameter. Right ventricular mass and wall thickness were restored in the mitochondrial group. In the pulmonary arteries of rats that received mitochondrial treatment, vascular smooth muscle cells expressed higher levels of α-smooth muscle actin and smooth muscle myosin heavy chain II, indicating the maintenance of the nonproliferative, contractile phenotype. The hyper-reactivity of isolated pulmonary arteries to α-adrenergic stimulation was also attenuated after mitochondrial transplantation. ConclusionsTransplantation of viable mitochondria can restore the contractile phenotype and vasoreactivity of the pulmonary artery, thereby reducing the afterload and right ventricular remodeling in rats with established pulmonary hypertension. The improvement in overall right ventricular performance suggests that mitochondrial transplantation can be a revolutionary clinical therapeutic option for the management of pulmonary hypertension.

Osthole inhibits cell proliferation by regulating the TGF-β1/Smad/p38 signaling pathways in pulmonary arterial smooth muscle cells

Pulmonary artery smooth muscle cell (PASMC) proliferation contributes to pulmonary vascular remodeling, which ultimately leads to pulmonary arterial hypertension (PAH). Osthole has been previously shown to inhibit tumor cell growth. Our previous experiments demonstrated that osthole could prevent monocrotaline-induced PAH and pulmonary artery remodeling in rats and that its effects might be associated with inhibiting PASMC proliferation. However, the exact mechanism remains unclear. In this study, we observed the inhibitory effect of osthole on platelet-derived growth factor (PDGF)-BB-induced rat PASMC growth, cell cycle progression and proliferating cell nuclear antigen (PCNA) expression, as measured by CCK-8 assay, flow cytometric analysis and western blotting, respectively. We also detected the expression and activities of the cell cycle regulators cyclin D1/CDK4, cyclin E1/CDK2, p53, p27 and p21 and the TGF-β1/Smad/p38 signaling pathways in rat PASMCs by western blotting. Our results show that osthole effectively suppressed PDGF-BB-stimulated proliferation, PCNA protein expression, and cell cycle progression in rat PASMCs in vitro. We further demonstrated that treatment with osthole significantly induced cell cycle arrest at the G0/G1 phase in PASMCs, which was supported by the finding that osthole significantly decreased cyclin D1/CDK4 and cyclin E1/CDK2 protein levels and increased p53, p27 and p21 protein levels. These effects may partly be attributed to the downregulation of TGF-β1/Smad/p38 signaling pathway activation. Our findings suggest that osthole is a potential therapeutic candidate that warrants further investigation regarding its potential use for the treatment of PAH.

STVNa attenuates right ventricle hypertrophy and pulmonary artery remodeling in rats induced by transverse aortic constriction

Right heart failure and pulmonary artery remodeling resulting from increased left heart pressure are prevalent in a clinical setting, and the specific pathological feature exhibits cancer-like cell proliferation in lung. STVNa has been previously demonstrated its anti-proliferation property. In this study, we want to verify the therapeutic effect of STVNa against right ventricle hypertrophy and pulmonary artery remodeling in rats induced by transverse aortic constriction (TAC). The results show that TAC surgery increased mean right ventricle pressure (mRVP) less in the STVNa group than that in the vehicle group (11.81 vs 22.71 mmHg/ml, p < 0.01). STVNa treatment reduced the right ventricle cardiomyocyte area (p < 0.05) and the proliferation of pathological smooth muscle cells proving by PCNA immunohistochemical staining. Gene expression of brain natriuretic peptide (BNP), smooth muscle actin (SMA) and CD31 assessed by real-time polymerase chain reaction were confirmed the above results. Also, STVNa treatment decreased the lung fibrosis content and alleviated the inflammation infiltration. The expression of ET-1 and the phosphorylation of signal-regulated kinase (ERK) were lower in STVNa group compared to vehicle group (p < 0.05). In summary, STVNa could relieve right ventricle hypertrophy and pulmonary artery remodeling formation in rats after 9 weeks of TAC surgery by reducing ET-1 expression and suppressing ERK phosphorylation signal and subsequently inhibiting cell proliferation.

Activation of peroxisome proliferator-activated receptor γ ameliorates monocrotaline-induced pulmonary arterial hypertension in rats.

Activation of peroxisome proliferator-activated receptor γ (PPARγ) suppresses the proliferation of pulmonary artery smooth muscle cells (PASMCs) and vascular remodeling in rats and humans, and therefore improves the development of pulmonary arterial hypertension (PAH). However, molecular mechanisms underlying these effects have not been completely understood. In the present study, the effects of PPARγ activation in monocrotaline (MCT)-induced pulmonary artery remodeling in rats were investigated. Eighteen Sprague-Dawley (SD) rats were randomly assigned into three groups (n=6): Control (Con), PAH and PAH treated with rosiglitazone (MCT + Rosi). The right ventricular systolic pressure (RVSP), the ratio of the right to left ventricle plus septum weight [RV/(LV + S)], the percentage of medial wall thickness (%MT) and wall area (%WA) were used to evaluate the development of PAH. Tissue morphology was measured using hematoxylin and eosin staining. The protein levels of the phosphatase and tensin homologue deleted on chromosome ten (PTEN), Akt (ser473) phosphorylation (p-Akt) and total Akt in intrapulmonary arteries were determined by western blot analysis. MCT treatment significantly increased the RVSP, which was reduced by rosiglitazone treatment. The ratio of RV/(LV + S), %MT and %WA induced by MCT were similarly inhibited, which was associated with the increase of PTEN expression and the inhibition of Akt phosphorylation levels by rosiglitazone. In conclusion, activation of PPARγ ameliorates the proliferation of PASMCs and vascular remodeling by regulating the PTEN/PI3K/Akt pathway, suggesting that the activation of PPARγ has potential benefits for PAH.

The effect of PS-341 on pulmonary vascular remodeling in high blood flow-induced pulmonary hypertension

The aim of the present study was to investigate the effects of PS-341 on vascular remodeling in an experimental rat model of high blood flow-induced pulmonary arterial hypertension (PAH), as well as to elucidate its mechanisms of action. We established the PAH model by a surgical method that implanted a left-to-right shunt. Three days post-surgery, the animals were randomly assigned to 3 groups (n=15 in each group): sham-operated (control), shunt (model) and PS-341 (treated) groups. Eight weeks post-surgery, hemodynamic parameters were significantly improved in the PS-341 group compared with the shunt group (P<0.05). Immunohistochemical analysis indicated that the expression levels of ubiquitin and nuclear factor-κB (NF-κB) p65 were significantly higher in the shunt group compared with the sham-operated group (P<0.05). Semi-quantitative western blot analysis further confirmed that the levels of ubiquitin and NF-κB p65 were decreased, while those of IκB-α (an inhibitor of NF-κB) were significantly increased in the PS-341 group compared with the shunt group (P<0.05). In conclusion, PS-341 attenuates high blood flow-induced pulmonary artery remodeling in rats via inhibition of the NF-κB pathway.

Serotonin inhibits apoptosis of pulmonary artery smooth muscle cells through 5-HT2A receptors involved in the pulmonary artery remodeling of pulmonary artery hypertension

ABSTRACTDecreased pulmonary artery smooth muscle cell (PASMC) apoptosis play a key role in pulmonary artery remodeling during pulmonary artery hypertension (PAH), but the mechanisms involved are unclear. Serotonin (5-HT) inhibits apoptosis in many pathologic processes by activating the 5-HT2A receptor. Therefore, we hypothesized that 5-HT may be the promoter of decreased apoptosis in PAH through the 5-HT2A receptor. We found that inhibition of the 5-HT2A receptor prevented the increase in pulmonary artery pressure and pulmonary artery remodeling in rats stimulated by monocrotaline. This effect was accompanied by increased apoptosis in the pulmonary artery. Cultured PASMCs stimulated with 5-HT showed a decrease in apoptosis with increased phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), pyruvate dehydrogenase kinase (PDK), and mitochondrial transmembrane potential. These effects were markedly prevented by a 5-HT2A receptor inhibitor, an ERK1/2 activation inhibitor peptide I, or a PDK inhibitor. In conclusion, 5-HT inhibited PASMC apoptosis by activating the 5-HT2A receptor through the pERK1/2 and PDK pathways.5-HT decreasing apoptosis through 5-HT2A receptor is involved, at least in part, in pulmonary artery remolding.

Effects of exercise on monocrotaline-induced changes in right heart function and pulmonary artery remodeling in rats

Pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) is an experimental protocol of right heart failure. We analyzed the role of exercise training on the right ventricle structure and function, pulmonary artery remodeling, and GSK-3β expression. Rats were divided among the following groups: sedentary control (SC), sedentary monocrotaline (SM), trained control (TC), and trained monocrotaline (TM). Rats underwent exercise training for a period of 5 weeks, with 3 weeks post-MCT injection. Rats in the SM and TM groups presented with an increase in right ventricle hypertrophy indexes and lung congestion. The right ventricular end diastolic pressure (RVEDP), right ventricular systolic pressure (RVSP), and its minimum and maximal pressure derivates were increased in the SM and TM groups. The right ventricle interstitial volume pulmonary artery thickness and p-GSK-3β/GSK-3β were increased in the MCT groups as compared with the control groups. The TM group had a reduction in interstitial volume, p-GSK-3β/GSK-3β ratio, pulmonary artery thickness, RVEDP, and an increase in intramyocardial vessels volume as compared with the SM group. The overall results have shown that the exercise protocol used promoted positive changes in right ventricle and pulmonary artery remodeling. These observations also suggest that structural remodeling may be influenced by signaling proteins, such as GSK-3β.

Effects of Atorvastatin and Losartan on Monocrotaline-Induced Pulmonary Artery Remodeling in Rats

Structural remodeling of pulmonary artery plays an important role in maintaining sustained pulmonary arterial hypertension (PAH). The anti-remodeling effects of statins have been reported in systemic hypertension. In this study, we studied the effects of atovastatin (Ato) or losartan (Los) in monocrotaline (MCL)-induced pulmonary artery remodeling using a rat model. Forty Sprague-Dawley (SD) rats were randomly assigned into four groups (n == 10): normal control (Ctr), PAH, PAH treated with Los, and PAH treated with Ato. We found that in the Los- or Ato-treated group, the mean pulmonary arterial pressure, right heart hypertrophy index, ratio of wall//lumen thickness (WT%%), as well as the wall//lumen area (WA%%) were significantly reduced compared to the PAH group. Also in pulmonary arteries dissected from rats in the Ato- or Los-treated group, in both mRNA and protein levels, the expression of α1C subunit of voltage-gated calcium channel (Cavα1c) was downregulated, while sarcoplasmic//endoplasmic reticulum calcium-ATPase (SERCA-2a) and inositol 1,4,5 triphosphate receptor 1 (IP3R-1) upregulated. However, the mRNA level of RyR-3 subunit of calcium regulating channel was increased, whereas its protein level was reduced in the treated groups. Our results suggest that atorvastatin or losartan may regress the remodeling of the pulmonary artery in pulmonary hypertensive rats, with differential expression of calcium regulating channels.

Effects of atorvastatin and losartan on monocrotaline-induced pulmonary artery remodeling in rats

Structural remodeling of pulmonary artery plays an important role in the maintaining of sustained pulmonary arterial hypertension (PAH). The anti-remodeling effects of statins have been reported in systemic hypertension. In this study, we investigated the effects of Ato and losartan (Los) on monocrotaline-induced pulmonary artery remodeling in rats. Forty SD rats were assigned into: normal control (Ctr), PAH, Los, Ato treated groups. The mean pulmonary arterial pressure was reduced by Los and Ato treatment (mmHg: PAH, 36.1 4.2; Los, 29.8 4.8; Ato, 27.6 4.1; P<0.05).

Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats

Accumulating evidences have demonstrated that RhoA/Rho-kinase pathway plays a pivotal role in various cellular functions. The aim of this study was to explore whether RhoA/Rho-kinase pathway is involved in the pathogenesis of high flow induced pulmonary hypertension and whether long-term inhibition of RhoA/Rho-kinase pathway with fasudil could attenuate high flow induced pulmonary artery remodeling in rats. Wistar rats in the shunt groups and treated groups were underwent left common carotid artery–external jugular vein shunt operation, rats in control groups were sham-operated animals. Rats in treated groups received fasudil treatment, the others received same dose of saline. At week 4, 8 of the study, rats were underwent haemodynamics measurements, pulmonary artery morphologic assessments, detection of pulmonary artery smooth muscle cells (SMCs) proliferation and apoptosis. RhoA and Rho-kinase activity in pulmonary arteries were also analyzed. Compared with the control groups, exposure to high blood flow induced a significant elevation of right ventricle systolic pressure at week 8, significant increase of the mean percentage of media wall thickness (%MT) in moderate size pulmonary arteries both at weeks 4 and 8, marked elevation of right ventricle (RV) to left ventricle plus septum (LV + SP) weight ratio at week 8, significant increase of PCNA-positive SMCs percentage at week 4 and significant decrease of TUNEL-positive SMCs percentage both at weeks 4 and 8. High pulmonary blood flow also induced 3.19 ± 0.28-fold increase of RhoA and 3.63 ± 0.52-fold increase of Rho-kinase over the control group at week 4, 1.57 ± 0.35-fold increase of RhoA and 2.36 ± 0.39-fold increase of Rho-kinase over the control group at week 8. Compared with the shunt groups, fasudil treatment significantly suppressed Rho-kinase activity at both weeks 4 and 8, improved pulmonary hypertension at week 8, attenuated right ventricular hypertrophy at week 8, and enhanced pulmonary vascular remodeling both at weeks 4 and 8, which were associated with suppressed pulmonary artery smooth muscle cells proliferation at week 4 and apoptosis both at weeks 4 and 8. These results indicated that RhoA/Rho-kinase mediated pathway participated in the process of high flow induced pulmonary artery remodeling; inhibition of Rho kinase with fasudil could attenuate pulmonary artery remodeling.