Vascular Smooth Muscle Proliferation Research Articles

Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease.

Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5' GMP (cGMP) signaling plays a central role in regulation of diverse processes including smooth muscle relaxation, inflammation, and fibrosis. sGC is activated by the short-lived physiologic mediator NO. sGC stimulators are small-molecule compounds that directly bind to sGC to enhance NO-mediated cGMP signaling. Olinciguat, (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide, is a new sGC stimulator currently in Phase 2 clinical development. To understand the potential clinical utility of olinciguat, we studied its pharmacokinetics, tissue distribution, and pharmacologic effects in preclinical models. Olinciguat relaxed human vascular smooth muscle and was a potent inhibitor of vascular smooth muscle proliferation in vitro. These antiproliferative effects were potentiated by the phosphodiesterase 5 inhibitor tadalafil, which did not inhibit vascular smooth muscle proliferation on its own. Olinciguat was orally bioavailable and predominantly cleared by the liver in rats. In a rat whole body autoradiography study, olinciguat-derived radioactivity in most tissues was comparable to plasma levels, indicating a balanced distribution between vascular and extravascular compartments. Olinciguat was explored in rodent models to study its effects on the vasculature, the heart, the kidneys, metabolism, and inflammation. Olinciguat reduced blood pressure in normotensive and hypertensive rats. Olinciguat was cardioprotective in the Dahl rat salt-sensitive hypertensive heart failure model. In the rat ZSF1 model of diabetic nephropathy and metabolic syndrome, olinciguat was renoprotective and associated with lower circulating glucose, cholesterol, and triglycerides. In a mouse TNFα-induced inflammation model, olinciguat treatment was associated with lower levels of endothelial and leukocyte-derived soluble adhesion molecules. The pharmacological features of olinciguat suggest that it may have broad therapeutic potential and that it may be suited for diseases that have both vascular and extravascular pathologies.

Adenosine kinase is critical for neointima formation after vascular injury by inducing aberrant DNA hypermethylation.

Adenosine receptors and extracellular adenosine have been demonstrated to modulate vascular smooth muscle cell (VSMC) proliferation and neointima formation. Adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels but is function in VSMC remains unclear. Here, we investigated the role of ADK in vascular injury-induced smooth muscle proliferation and delineated the mechanisms underlying its action. We found that ADK expression was higher in the neointima of injured vessels and in platelet-derived growth factor-treated VSMCs. Genetic and pharmacological inhibition of ADK was enough to attenuate arterial injury-induced neointima formation due to inhibition of VSMC proliferation. Mechanistically, using infinium methylation assays and bisulfite sequencing, we showed that ADK metabolized the intracellular adenosine and potentiated the transmethylation pathway, then induced the aberrant DNA hypermethylation. Pharmacological inhibition of aberrant DNA hypermethylation increased KLF4 expression and suppressed VSMC proliferation as well as the neointima formation. Importantly, in human femoral arteries, we observed increased ADK expression and DNA hypermethylation as well as decreased KLF4 expression in neointimal VSMCs of stenotic vessels suggesting that our findings in mice are relevant for human disease and may hold translational significance. Our study unravels a novel mechanism by which ADK promotes VSMC proliferation via inducing aberrant DNA hypermethylation, thereby down-regulating KLF4 expression and promoting neointima formation. These findings advance the possibility of targeting ADK as an epigenetic modulator to combat vascular injury.

Curcumin inhibits proliferation, migration and neointimal formation of vascular smooth muscle via activating miR-22

Context Curcumin has antitumor, antioxidative, anti-inflammatory, and anti-proliferative properties. Objective To investigate the role of miR-22 during curcumin-induced changes in vascular smooth muscle cells (VSMC) and neointima formation in balloon-injured rat abdominal aorta. Materials and methods Sprague-Dawley rats were randomised to the sham-operated (n = 10), operated control (injured, n = 10), and curcumin treatment (n = 10) groups. miR-22 expression was determined by real-time PCR. SP1 was assessed by western blot and real-time PCR. Rat aortic smooth muscle A7r5 cells were used to determine VSMC proliferation and migration, which were measured by the MTS, EdU staining, Transwell, and wound healing assays. Results miR-22 levels declined following arterial balloon injury in vivo (48% at 3d, p < 0.05) and serum stimulation in vitro (45% at 24 h, p < 0.01). Functional studies revealed that miR-22 negatively regulated the proliferation and migration of VSMCs by directly targeting the SP1 transcription factor in VSMCs. Curcumin increased the expression of miR-22 (81%, p < 0.05) and decreased the protein expression of SP1 in VSMCs (25%, p < 0.05). miR-22 inhibition was found to attenuate the effects of curcumin on VSMC functions. Curcumin increased miR-22 (46%, p < 0.01), decreased the SP1 protein (19%, p < 0.05), and inhibited vascular neointimal area (48%, p < 0.01) in vivo. Discussion The miR-22/SP1 pathway is involved in the protective role of curcumin during arterial balloon injury, but the mechanisms remain unclear. Conclusion miR-22 is involved in the inhibitory effects of curcumin on VSMCs’ proliferation, migration and neointima hyperplasia after arterial balloon injury in rats. Curcumin could be used to prevent neointimal hyperplasia after angioplasty.

Thymine DNA glycosylase is a key regulator of CaMKIIγ expression and vascular smooth muscle phenotype.

Multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multigene family with isoform-specific regulation of vascular smooth muscle (VSM) functions. In previous studies, we found that vascular injury resulted in VSM dedifferentiation and reduced expression of the CaMKIIγ isoform in medial wall VSM. Smooth muscle knockout of CaMKIIγ enhanced injury-induced VSM neointimal hyperplasia, whereas CaMKIIγ overexpression inhibited VSM proliferation and neointimal formation. In this study, we evaluated DNA cytosine methylation/demethylation as a mechanism for regulating CaMKII isoform expression in VSM. Inhibition of cytosine methylation with 5-Aza-2'-deoxycytidine significantly upregulated CaMKIIγ expression in cultured VSM cells and inhibited CaMKIIγ downregulation in organ-cultured aorta ex vivo. With the use of methylated cytosine immunoprecipitation, the rat Camk2g promoter was found hypomethylated in differentiated VSM, whereas injury- or cell culture-induced VSM dedifferentiation coincided with Camk2g promoter methylation and decreased expression. We report for the first time that VSM cell phenotype switching is accompanied by marked induction of thymine DNA glycosylase (TDG) protein and mRNA expression in injured arteries in vivo and in cultured VSM synthetic phenotype cells. Silencing Tdg in VSM promoted expression of CaMKIIγ and differentiation markers, including myocardin, and inhibited VSM cell proliferation and injury-induced neointima formation. This study indicates that CaMKIIγ expression in VSM is regulated by cytosine methylation/demethylation and that TDG is an important determinant of this process and, more broadly, VSM phenotype switching and function.NEW & NOTEWORTHY Expression of the calcium calmodulin-dependent protein kinase II-γ isoform (CaMKIIγ) is associated with differentiated vascular smooth muscle (VSM) and negatively regulates proliferation in VSM synthetic phenotype (VSMSyn) cells. This study demonstrates that thymine DNA glycosylase (TDG) plays a key role in regulating CaMKIIγ expression in VSM through promoter cytosine methylation/demethylation. TDG expression is strongly induced in VSMSyn cells and plays key roles in negatively regulating CaMKIIγ expression and more broadly VSM phenotype switching.

Long non‑coding RNA MALAT1 sponges miR‑124‑3p.1/KLF5 to promote pulmonary vascular remodeling and cell cycle progression of pulmonary artery hypertension.

Previous studies have demonstrated that long non-coding RNA (lncRNA) is involved in vascular remodeling. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) lncRNA is associated with the proliferation and migration of vascular smooth muscle and endothelial cells; however, its biological role in pulmonary artery hypertension (PAH) is currently unclear. The aim of the present study was to investigate the post-transcriptional regulation of MALAT1 in human pulmonary artery smooth muscle cells (HPASMCs). The results revealed that MALAT1 expression levels were significantly upregulated in the pulmonary arteries (PAs) and HPASMCs obtained from patients with PAH compared with adjacent normal PA tissues and HPASMCs. Knockdown of MALAT1 suppressed the viability and proliferation of HPASMCs and prevented cells entering the G0/G1 cell cycle phase. MALAT1 overexpression exerted the opposite effects. Bioinformatics analysis predicted complementary binding of hsa-microRNA (miR)-124-3p.1 with the 3′-untranslated region of MALAT1. Luciferase reporter assays and RNA immunoprecipitation experiments demonstrated molecular binding between MALAT1 and hsa-miR-124-3p.1. This resulted in the formation of an RNA-induced silencing complex. In addition, Kruppel-like factor 5 (KLF5) was confirmed to be a target gene of MALAT1/hsa-miR-124-3p.1. MALAT1 silencing did not inhibit the proliferation and migration of HPASMCs following knockdown of hsa-miR-124-3p.1. In addition, MALAT1 knockdown was demonstrated to attenuate the expression of KLF5. Following MALAT1 knockdown, the expression level of KLF5 was rescued by inhibition of hsa-miR-124-3p.1 expression. The results of the current study indicate that the MALAT1/hsa-miR-124-3p.1/KLF5 axis may serve a key role in HPASMCs. In addition, the results contribute to what is known regarding the role of MALAT1 in PAH development and provide a novel theoretical basis for the development of new therapeutic interventions for patients with PAH.

MicroRNA-15b participates in the development of peripheral arterial disease by modulating the growth of vascular smooth muscle cells.

As an atherosclerotic disease, the process of peripheral arterial disease (PAD) is complicated and includes the abnormal proliferation of vascular smooth muscle. The current study aimed to determine the role of microRNA-15b (miR-15b) in the development of PAD and its associated mechanisms. Human vascular smooth muscle cells (hVSMCs) were used in the current study. To assess the effects of miR-15b on hVSMCs, miR-15b was up- or downregulated in hVSMCs using miR-15b mimics or miR-15b inhibitors respectively. Cell viability, migration and apoptosis were then determined via MTT, transwell and flow cytometry assays, respectively. TargetScan bioinformatics software was utilized to predict the targets of miR-15b, and the binding sites between insulin growth factor 1 receptor (IGF1R) and miR-15b were confirmed by dual-luciferase reporter assay. The results reveled that the miR-15b mimic significantly reduced hVSMC cell viability and migration, and promoted cell apoptosis. However, the opposite effect was observed following miR-15b inhibitor transfection. It was also determined that miR-15b directly targeted IGF1R and negatively regulated its expression in hVSMCs. Additionally, the results demonstrated that the miR-15b mimic inhibited the PI3K/AKT signaling pathway in hVSMCs, whereas the miR-15b inhibitor promoted it. Furthermore, the results indicated that the effect of the miR-15b mimic on hVSMCs was reversed by IGF1R overexpression. In conclusion, the data indicated that miR-15b participated in the occurrence and development of PAD by modulating hVSMC proliferation, apoptosis and migration via the regulation of IGF1R expression.

Circular RNA circCHFR Facilitates the Proliferation and Migration of Vascular Smooth Muscle via miR-370/FOXO1/Cyclin D1 Pathway

Circular RNA (circRNA) is a novel subgroup of noncoding RNA in the human transcriptome playing a vital role in the atherosclerosis of cerebrovascular disease. However, the in-depth mechanism by which circRNA regulates the vascular smooth muscle proliferation and migration is still elusive. Here, a novel identified circRNA, circCHFR, was validated to be aberrantly overexpressed in the ox-LDL-induced vascular smooth muscle cell (VSMCs). Functionally, the circCHFR silencing by oligonucleotide transfection suppressed the proliferation and migration ability of VSMCs. Mechanically, bioinformatics tools and luciferase reporter assay state that circCHFR acts as a sponge of miR-370, and miR-370 targets the 3′ UTR of FOXO1. Furthermore, the transcription factor FOXO1 could bind with the promoter region of CCND1 mRNA and promote Cyclin D1 expression. In summary, this finding states the vital role of the circCHFR/miR-370/FOXO1/Cyclin D1 axis and provides a profound understanding about the circRNA in smooth muscle cells and atherosclerosis.

Poldip2 knockdown inhibits vascular smooth muscle proliferation and neointima formation by regulating the expression of PCNA and p21

Polymerase delta-interacting protein 2 (Poldip2) is a multi-functional protein with numerous roles in the vasculature, including the regulation of cell apoptosis and migration, as well as extracellular matrix deposition; however, its role in VSMC proliferation and neointimal formation is unknown. In this study, we investigated the role of Poldip2 in intraluminal wire-injury induced neointima formation and proliferation of vascular smooth muscle cells in vitro and in vivo. Poldip2 expression was observed in the intima and media of human atherosclerotic arteries, where it colocalized with proliferating cell nuclear antigen (PCNA). Wire injury of femoral arteries of Poldip2+/+ mice induced robust neointimal formation after 2 weeks, which was impaired in Poldip2+/‒ mice. PCNA expression was significantly reduced and expression of the cell cycle inhibitor p21 was significantly increased in wire-injured arteries of Poldip2+/‒ animals compared to wild-type controls. No difference was observed in apoptosis. Downregulation of Poldip2 in rat aortic smooth muscle cells significantly reduced serum-induced proliferation and PCNA expression, but upregulated p21 expression. Downregulation of p21 using siRNA reversed the inhibition of proliferation induced by knockdown of Poldip2. These results indicate that Poldip2 plays a critical role in the proliferation of VSMCs.

Role of SOD3 in silica-related lung fibrosis and pulmonary vascular remodeling

BackgroundWork-place exposure to silica dust may lead to progressive lung inflammation culminating in the development of silicosis, an irreversible condition that can be complicated by onset of pulmonary hypertension (PH). The molecular mechanisms leading to the development of PH and lung fibrosis in response to silica are not well understood. Oxidant/antioxidant imbalance in the lung may promote fibroproliferation and vascular smooth muscle proliferation, ultimately leading to the development of PH. Herein, we analyze the development of PH and lung fibrosis in mice deficient in extracellular superoxide dismutase (SOD3), an enzyme with anti-oxidant activity.MethodsPH and silicosis were induced in wild-type and Sod3−/− mice through intratracheal injection of crystalline silica at dose 0.4 g/kg. Pulmonary hypertension and lung fibrosis were characterized by changes in right ventricular systolic pressure (RVSP) and collagen deposition 28 days following silica injections. Vascular remodeling was analyzed using immunohistochemistry and morphometric analysis. The expression of genes were analyzed using qRT-PCR and Western blot.ResultsC57BL6 mice exposed to silica showed attenuated expression of Sod3 in the lung suggesting a protective role for Sod3. Consistent with this, Sod3−/− mice developed more severe fibrotic inflammatory nodules with increased collagen deposition. Furthermore, the expression of genes involved in tissue remodeling (Timp1), fibrotic lesion formation (Fsp1) and inflammatory response (Mcp1) were significantly elevated in Sod3−/− mice compared to Sod3+/+ mice treated with silica. Infiltration of neutrophils and activated macrophages into affected lung was significantly higher in Sod3 deficient mice. In addition, silica produced more profound effects on elevation of RVSP in Sod3−/− compared to wild-type littermate. Increase in RVSP was concomitant with hypertrophy of pulmonary arteries located in silicotic nodules of both mouse strains, however, vascular remodeling in unaffected areas of lung was detected only in Sod3−/− mice.ConclusionsOur data suggest that Sod3 and extracellular oxidative stress may play an important role in the development of pneumoconiosis and pulmonary vascular remodeling following exposure to environmental and occupational silica.

The protective mechanism of D-pinitol on advanced glycation end products-induced proliferation and migration in vascular smooth muscle cells

Objective To investigate the effect and its mechanism of D-pinitol on advanced glycation end products(AGEs)-induced proliferation and migration in mouse aortic vascular smooth muscle cells(VSMC). Methods VSMCs were isolated from mouse aorta and cultured in vitro.Effects of different concentrations of D-pinitol on proliferation and migration of VSMCs were observed by using the AGEs-induced glycosylation injury model of VSMCs.Cell proliferation and migration were detected by CCK-8 assay and cell scratch, respectively.The protein expression levels of transforming growth factor-β1(TGF-β1), p-smad2, p-smad3 and asporin were determined by Western blot. Results Compared with control group, AGEs group showed the increased protein expression levels of asporin, TGF-β1, p-smad2 and p-smad3(40.06±4.50 vs.17.47±0.57), (55.25±2.07 vs.14.42±2.07), (0.97±0.02 vs.0.47±0.02), (0.45±0.01 vs.0.26±0.02), all P<0.01.Compared to AGEs group, D-pinitol group could inhibit the cell proliferation and migration and cause dose-dependent decreases of protein expressions of TGF-β1, p-smad2, p-smad3 and asporin(P<0.05 or P<0.01). Conclusions D-pinitol can inhibit AGEs-induced cell proliferation and migration in mouse aortic VSMCs.Asporin may participate in the VSMCs extracellular matrix remodeling via TGF-β/smad pathway. Key words: D-pinitol; Muscle, smooth, vascular; Glycosylation end products, advanced; Extracellular matrix

Role of NLRP-3 Inflammasome in Hypertension: A Potential Therapeutic Target.

Hypertension is a multifactorial and chronic cardiovascular condition whose complications are responsible for worldwide morbidity and mortality. An increasing body of experimental data, recognize low-grade inflammation as a basic process in hypertension onset and development since there is a strong contribution of both the innate and the adaptive immune system according to the so-called Danger-Model. In this contest, NLRP3 inflammasome represents a key signaling platform as demonstrated by its implication in several hypertension-associated conditions, such as vascular smooth muscle remodeling and proliferation. This intracellular receptor is activated by Pathogenassociated molecular pattern molecules/damage-associated molecular pattern molecules signals and its mechanism of action converges on the final production of caspase-1 and, consequently, of the proinflammatory cytokines IL-1β and IL-18. The aim of the present work was to point out the role of the NLRP3 inflammasome complex in the hypertensive pathology and to describe it as a new potential therapeutic target. A systematic review of the literature data related to NLRP3 and hypertension correlation has been performed. Numerous and well-designed experiments demonstrate that the inflammasome plays a crucial role in essential and high-salt dependent hypertension, as well as in preeclampsia, in pulmonary hypertension, and in its related secondary disorders; its mechanism includes both a central nervous and a peripheral modulation of the inflammatory pathways. To date, research is trying to design inflammasome antagonists or equivalent inhibition strategies. The inflammasome represents a leading promoter of hypertensive inflammation opening new perspective in the field of the clinical approach in this pathology.

Haem oxygenase-1 inhibits neointimal hyperplasia in rat by histone deacetylase 2

It has been reported that haem oxygenase-1 (Hmox1) induction attenuates neointimal thickening. Here we further investigated the potential mechanisms regulating this important pathological process. We revealed that histone deacetylase 2 (HDAC2) was induced following Hmox1 induction under 1% oxygen treatment and this induction was attenuated after the treatment of siRNA against Hmox1. Interestingly, this HDAC2 induction was dependent on Hmox1 protein as well as its enzymatic activity, and was regulated by carbon monoxide released from haem degradation. Furthermore, histone deacetylase inhibitor, trichostatin A, successfully abrogated the inhibitory effects of vascular smooth muscle migration and proliferation by Hmox1 induction in vitro. In a rat carotid balloon injury model, similar results were observed by measuring neointimal thickening. As such, we concluded that Hmox1 inhibits neointimal hyperplasia via HDAC2 in rats.

Research progress on the roles of Krüppel-like factors in muscle tissues

Krüppel-like factors (KLFs) are a group of transcription factors characterized with three C2H2 zinc fingers at C-terminus. The N-termini of KLFs are highly variable and usually work as a transcriptional regulatory domain. The N-termini of KLFs may also bind to cofactors and change the transcriptional regulation abilities of KLFs. KLFs play important roles in the differentiation and phenotype maintenance of various cells. Additionally, KLFs are involved in the regulation of human physiological processes and in the occurrence and development of the diseases. There are 18 kinds of KLFs identified in human genome. The current reports show that several KLFs regulate the development and functions of the three kinds of muscle tissues in humans and animals. In cardiac muscle, KLF4, KLF10, KLF11 and KLF15 are involved in the negative regulation of cardiac hypertrophy. In addition, KLF6 is involved in the regulation of cardiac fibrosis. KLF13 regulates cardiac muscle development during the embryonic period. In vascular smooth muscle, the post-translated modification of KLF4 is regulated by positive factors of cell proliferation and differentiation and plays important roles in the regulation of the vascular smooth muscle phenotype. In addition, KLF5 promotes vascular smooth muscle proliferation, while KLF8 and KLF15 inhibit vascular smooth muscle proliferation. In skeletal muscle, KLF2, KLF3, KLF4, KLF10 and KLF15 are involved in the regulation of skeletal muscle development. Notably, KLF15 influences the energy metabolism in three kinds of muscle tissues. In conclusion, several KLFs may have the same regulatory mechanism in two or three kinds of muscle tissues. In the same kind of muscle tissue, the synergistic and sequential regulation among KLFs may occur and be important for the development and function regulation of muscle tissues. In this review, we summarize the research progress on the functions and mechanism of KLFs in cardiac muscle, smooth muscle, and skeletal muscle. It also provides references for the further understanding of the functions of KLFs in muscle tissues and reveals the molecular mechanisms of muscle-related diseases.

Midkine levels and its relationship with atherosclerotic risk factors in essential hypertensive patients.

Hypertension (HT) is one of the risk factors associated with atherosclerosis. Midkine (MK) plays a role as a growth factor in various biologic and pathologic events. In some reports, MK expression has been shown to be linked with vascular smooth muscle proliferation and neo-angiogenesis in atherosclerotic vessels. The aim was to research relationship of MK serum levels with some atherosclerotic risk factors in hypertensive patients. This study examined 60 patients with essential HT and 30 healthy controls. Serum biochemistry, including lipid profile, MK, Vitamin B12, C-reactive protein, zinc and copper levels were obtained. MK levels of the HT patients were significantly higher than the control group (24.8 ± 6.8 ng/mL vs. 18.39 ± 5.6 ng/mL, respectively, P < 0.01). Lipid profile parameters such as total cholesterol, triglyceride, low-density lipoprotein (LDL) were also significantly higher in HT patients (P < 0.021, P < 0.01, and P < 0.01, respectively). Zinc levels were 179.13 ± 34.06 μg/dL and 172.55 ± 45.47μg/dL in the HT and control group, respectively. Serum MK levels were positively correlated with diastolic (r = 0.288, P < 0.05) and systolic blood pressures (r = 0.390, P < 0.002), and also with serum total cholesterol (r = 0.406, P < 0.002) and LDL cholesterol (r = 0.318, P < 0.015) levels. Furthermore MK was also negatively correlated with zinc and Vitamin B12levels (r = -0.298, P < 0.023, r = -0.334, P < 0.027, respectively). This study has demonstrated an important association between increased serum MK levels and risk factors of atherosclerosis such as HT, increased total and LDL cholesterol.

Inhibition of Aortic Intimal Hyperplasia and Vascular Smooth Muscle Proliferation and Extracellular Matrix Protein Expressions by Astragalus-Angelica Combination.

VSMC proliferation and ECM deposition always resulted in intimal hyperplasia. Astragalus–Angelica combination has a protective effect on the cardiovascular system. The inhibition effect of different Astragalus–Angelica combination on the hyperplastic intima after vascular balloon injury in rats was investigated in this study. Astragalus–Angelica combination can inhibit the intima hyperplasia after balloon injury, in which a 1:1 ratio shows excellent results. Astragalus–Angelica combination can enhance the expression of smooth muscle α-actin (SMа-actin) and inhibit the expression of proliferating cell nuclear antigen (PCNA), cyclin D1, cyclin E, collagen I (Col-I), fibronectin (FN), and matrix metallopeptidase-9 (MMP-9) in hyperplastic intima, suggesting that Astragalus–Angelica combination can inhibit the intimal hyperplasia of blood vessels in rats. The mechanism is related to the inhibition of PI3K/Akt signaling pathway activation and thereby inhibits the phenotypic transformation and cell proliferation of VSMCs and thus inhibits the extracellular matrix (ECM) deposition of vascular wall during intimal hyperplasia.

The Role of Gap Junction in Regulating Vascular Function and Its Relationship with Hypertension

Gap junction (GJ), also called as gap connection, communication connection, is a special membrane structure which consisted of connecting channels in two adjacent cells. Intercellular communication can be divided into indirect and direct communication. Direct communication is a cell-to-cell communication mediated by GJ between adjacent cells. Direct communication is also called as gap junction intercellular communication (GJIC). Adjacent cells exchange information, energy, and substances by using direct communication. They participate in the metabolic coupling of cell-to-cell substances exchanges and the electrical coupling of electrical signals. They play important roles in regulating physiological processes including metabolism, homeostasis, proliferation, and vasodilation of vascular smooth muscle so on. This article will focus on introducing the progresses of studies on the morphology, structure and function of GJ in details. Blood pressure is the force exerted by the blood against the walls of the blood vessels. A blood pressure higher than 130 over 80 millimeters of mercury (mmHg) is defined as hypertension. Hypertension and heart disease are global diseases. Hypertension was correlated with many factors, which contributed to hypertension by many mechanisms including sodium, potassium, Gap junction and so on. The studies on GJ and hypertension were also introduced in details, such as hypertension and expression of Cx, Ca2+ and GJ, Genetic Polymorphism of Cx40 and Hypertension.

Loss of Spry1 attenuates vascular smooth muscle proliferation by impairing mitogen-mediated changes in cell cycle regulatory circuits.

Signals from growth factors or mechanical stimuli converge to promote vascular smooth muscle cell (VSMC) migration and proliferation, key events in the pathogenesis of intimal hyperplasia upon vascular injury. Spry1, a regulator of receptor tyrosine kinases (RTK), plays a role in maintaining the contractile phenotype of VSMC. The aim of the current study was to determine the role of Spry1 in VSMC proliferation in vitro and injury induced neointimal hyperplasia in vivo. VSMC proliferation and neointima formation were evaluated in cultured human aortic SMC (hAoSMC) and ligation-induced injury of mouse carotid arteries from Spry1 gene targeted mice, and their corresponding wild type littermates. Human Spry1 or non-targeting control lentiviral shRNAs were used to knock down Spry1 in hAoSMC. Time course cell cycle analysis showed a reduced fraction of S-phase cells at 12 and 24 h after growth medium stimulation in Spry1 shRNA transduced hAoSMC. Consistent with reduced S-phase entry, the induction of cyclinD1 and the levels of pRbS807/S811, pH3Ser10, and pCdc2 were also reduced, while the cell cycle inhibitor p27Kip1 was maintained in Spry1 knockdown hAoSMC. In vivo, loss of Spry1 attenuated carotid artery ligation-induced neointima formation in mice, and this effect was accompanied by a decrease in cell proliferation similar to the in vitro results. Our findings demonstrate that loss of Spry1 attenuates mitogen-induced VSMC proliferation, and thus injury-induced neointimal hyperplasia likely via insufficient activation of Akt signaling causing decreased cyclinD1 and increased p27Kip1 and a subsequent decrease in Rb and cdc2 phosphorylation.

Effects of age and exercise training on coronary microvascular smooth muscle phenotype and function.

Coronary microvascular function and blood flow responses during acute exercise are impaired in the aged heart but can be restored by exercise training. Coronary microvascular resistance is directly dependent on vascular smooth muscle function in coronary resistance arterioles; therefore, we hypothesized that age impairs contractile function and alters the phenotype of vascular smooth muscle in coronary arterioles. We further hypothesized that exercise training restores contractile function and reverses age-induced phenotypic alterations of arteriolar smooth muscle. Young and old Fischer 344 rats underwent 10 wk of treadmill exercise training or remained sedentary. At the end of training or cage confinement, contractile responses, vascular smooth muscle proliferation, and expression of contractile proteins were assessed in isolated coronary arterioles. Both receptor- and non-receptor-mediated contractile function were impaired in coronary arterioles from aged rats. Vascular smooth muscle shifted from a differentiated, contractile phenotype to a secretory phenotype with associated proliferation of smooth muscle in the arteriolar wall. Expression of smooth muscle myosin heavy chain 1 (SM1) was decreased in arterioles from aged rats, whereas expression of phospho-histone H3 and of the synthetic protein ribosomal protein S6 (rpS6) were increased. Exercise training improved contractile responses, reduced smooth muscle proliferation and expression of rpS6, and increased expression of SM1 in arterioles from old rats. Thus age-induced contractile dysfunction of coronary arterioles and emergence of a secretory smooth muscle phenotype may contribute to impaired coronary blood flow responses, but arteriolar contractile responsiveness and a younger smooth muscle phenotype can be restored with late-life exercise training. NEW & NOTEWORTHY Aging impairs contractile function of coronary arterioles and induces a shift of the vascular smooth muscle toward a proliferative, noncontractile phenotype. Late-life exercise training reverses contractile dysfunction of coronary arterioles and restores a young phenotype to the vascular smooth muscle.

Wnt signaling in cardiovascular disease: opportunities and challenges.

Cardiometabolic diseases increasingly afflict our aging, dysmetabolic population. Complex signals regulating low-density lipoprotein receptor-related protein (LRP) and frizzled protein family members - the plasma membrane receptors for the cadre of Wnt polypeptide morphogens - contribute to the control of cardiovascular homeostasis. Both canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) Wnt signaling programs control vascular smooth muscle (VSM) cell phenotypic modulation in cardiometabolic disease. LRP6 limits VSM proliferation, reduces arteriosclerotic transcriptional reprogramming, and preserves insulin sensitivity while LRP5 restrains foam cell formation. Adipose, skeletal muscle, macrophages, and VSM have emerged as important sources of circulating Wnt ligands that are dynamically regulated during the prediabetes-diabetes transition with cardiometabolic consequences. Platelets release Dkk1, a LRP5/LRP6 inhibitor that induces endothelial inflammation and the prosclerotic endothelial-mesenchymal transition. By contrast, inhibitory secreted frizzled-related proteins shape the Wnt signaling milieu to limit myocardial inflammation with ischemia-reperfusion injury. VSM sclerostin, an inhibitor of canonical Wnt signaling in bone, restrains remodeling that predisposes to aneurysm formation, and is downregulated in aneurysmal vessels by epigenetic methylation. Components of the Wnt signaling cascade represent novel targets for pharmacological intervention in cardiometabolic disease. Conversely, strategies targeting the Wnt signaling cascade for other therapeutic purposes will have cardiovascular consequences that must be delineated to establish clinically useful pharmacokinetic-pharmacodynamic relationships.

Role of mimecan in development of atherosclerosis induced by increased blood pressure variability

To examine the changes of mimecan protein expression in development of atherosclerosis induced by sinoaortic denervation, and to explore the effects of mimecan knock down on the proliferation and migration of vascular smooth muscle cells. Methods: The animals were randomly divided into a sham group and a model group (n=8 in each group). The rat model of blood pressure variability was established by sinoaortic denervation, and the hemodynamic indexes were recorded 20 weeks after the surgery to confirm the success of the model. The thoracic aorta was excised and stained with immunohistochemistry to observe the pathological changes of smooth muscle tissues and the changes of mimecan expression. The mice vascular smooth muscle cells were isolated, and which were treated with mimecan siRNA to knock down the mimecan expression. The cell proliferation was observed by 5-ethynyl-2'-deoxyuridine (Edu) in corporation test and the changes of cell migration was observed by wound healing test. Results: Twenty weeks after sinoaortic denervation, the blood pressure variability in the model group was significantly increased compared with that in the sham group, suggesting the model was successfully established. In addition, the increased blood pressure variability in the model group promoted the proliferation and migration of the vascular smooth muscle cells in thoracic aorta, while the expression of mimecan protein was significantly decreased. In in vitro assays, the knock down of mimecan in mice vascular smooth muscle cells could promote the cell proliferation and migration. Conclusion: Mimecan plays a protective role in the development of sinoaortic denervation induced atherosclerosis through amechanism involving suppression of the proliferation and migration of vascular smooth muscle cells.