Smooth Muscle Cells: A Novel Site of P-Selectin Expression with Pathophysiological and Therapeutic Relevance in Pulmonary Hypertension.
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ABSTRACT:
SUBMITTER: Sundd P
PROVIDER: S-EPMC6543715 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Persistent pulmonary hypertension of the newborn (PPHN) is one of the main causes of neonatal morbidity and mortality. It is characterized by sustained elevation of pulmonary vascular resistance (PVR), preventing an increase in pulmonary blood flow after birth. The affected neonates fail to establish blood oxygenation, precipitating severe respiratory distress, hypoxemia, and eventually death. Inhaled nitric oxide (iNO), the only approved pulmonary vasodilator for PPHN, constitutes, alongside supportive therapy, the basis of its treatment. However, nearly 40% of infants are iNO resistant. The cornerstones of increased PVR in PPHN are pulmonary vasoconstriction and vascular remodeling. A better understanding of PPHN pathophysiology may enlighten targeted and more effective therapies. Sildenafil, prostaglandins, milrinone, and bosentan, acting as vasodilators, besides glucocorticoids, playing a role on reducing inflammation, have all shown potential beneficial effects on newborns with PPHN. Furthermore, experimental evidence in PPHN animal models supports prospective use of emergent therapies, such as soluble guanylyl cyclase (sGC) activators/stimulators, l-citrulline, Rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, recombinant superoxide dismutase (rhSOD), tetrahydrobiopterin (BH4) analogs, ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs), 5-HT2A receptor antagonists, and recombinant human vascular endothelial growth factor (rhVEGF). This review focuses on current knowledge on alternative and novel pathways involved in PPHN pathogenesis, as well as recent progress regarding experimental and clinical evidence on potential therapeutic approaches for PPHN.
| S-EPMC7396717 | biostudies-literature
Project description:Emerging evidence suggests that caveolin-1 (Cav1) is associated with pulmonary arterial hypertension. MURC (also called Cavin-4) is a member of the cavin family, which regulates caveolar formation and functions together with caveolins. Here, we show that hypoxia increased Murc mRNA expression in the mouse lung, and that Murc-null mice exhibited attenuation of hypoxia-induced pulmonary hypertension (PH) accompanied by reduced ROCK activity in the lung. Conditional knockout mice lacking Murc in smooth muscle also resist hypoxia-induced PH. MURC regulates the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) through Rho/ROCK signalling. Cav1 suppresses RhoA activity in PASMCs, which is reversed by MURC. MURC binds to Cav1 and inhibits the association of Cav1 with the active form of Gα13, resulting in the facilitated association of the active form of Gα13 with p115RhoGEF. These results reveal that MURC has a function in the development of PH through modulating Rho/ROCK signalling.
| S-EPMC4996946 | biostudies-literature
Project description:Background and purposePulmonary arterial hypertension (PAH, type 1 pulmonary hypertension) has a 3-year survival of ~50% and is in need of new, effective therapies. In PAH, remodelling of the pulmonary artery (PA) increases pulmonary vascular resistance and can result in right heart dysfunction and failure. Genetic mutations can cause PAH but it can also be idiopathic (IPAH). Enhanced contractility and proliferation of PA smooth muscle cells (PASMCs) are key contributors to the pathophysiology of PAH, but the underlying mechanisms are not well understood.Experimental approachWe utilized RNA-sequencing (RNA-seq) of IPAH and control patient-derived PASMCs as an unbiased approach to define differentially expressed (DE) genes that may identify new biology and potential therapeutic targets.Key resultsAnalysis of DE genes for shared gene pathways revealed increases in genes involved in cell proliferation and mitosis and decreases in a variety of gene sets, including response to cytokine signalling. ADGRG6/GPR126, an adhesion G protein-coupled receptor (GPCR), was increased in IPAH-PASMCs compared to control-PASMCs. Increased expression of this GPCR in control-PASMCs decreased their proliferation; siRNA knockdown of ADGRG6/GPR126 in IPAH-PASMCs tended to increase proliferation.Conclusion and implicationsThese data provide insights regarding the expression of current and experimental PAH drug targets, GPCRs and GPCR-related genes as potentially new therapeutic targets in PAH-PASMCs. Overall, the findings identify genes and pathways that may contribute to IPAH-PASMC function and suggest that ADGRG6/GPR126 is a novel therapeutic target for IPAH.
| S-EPMC7348089 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is characterized by remodeling and narrowing of the pulmonary arteries, which lead to elevation of right ventricular pressure, heart failure, and death. Proliferation of pulmonary artery smooth muscle cells (PASMCs) is thought to be central to the pathogenesis of PAH, although the underlying mechanisms are still being explored. The protein p53 is involved in cell cycle coordination, DNA repair, apoptosis, and cellular senescence, but its role in pulmonary hypertension (PH) is not fully known. We developed a mouse model of hypoxia-induced pulmonary hypertension (PH) and found significant reduction of p53 expression in the lungs. Our in vitro experiments with metabolomic analyses and the Seahorse XF extracellular flux analyzer indicated that suppression of p53 expression in PASMCs led to upregulation of glycolysis and downregulation of mitochondrial respiration, suggesting a proliferative phenotype resembling that of cancer cells. It was previously shown that systemic genetic depletion of p53 in a murine PH model led to more severe lung manifestations. Lack of information about the role of cell-specific p53 signaling promoted us to investigate it in our mouse PH model with the inducible Cre-loxP system. We generated a mouse model with SMC-specific gain or loss of p53 function by crossing Myh11-Cre/ERT2 mice with floxed Mdm4 mice or floxed Trp53 mice. After these animals were exposed to hypoxia for 4 weeks, we conducted hemodynamic and echocardiographic studies. Surprisingly, the severity of PH was similar in both groups of mice and there were no differences between the genotypes. Our findings in these mice indicate that activation or suppression of p53 signaling in SMCs has a minor role in the pathogenesis of PH and suggest that p53 signaling in other cells (endothelial cells, immune cells, or fibroblasts) may be involved in the progression of this condition.
| S-EPMC6391010 | biostudies-literature
Project description:ObjectiveMutations in BMPR2 (bone morphogenetic protein receptor 2) are associated with familial and sporadic pulmonary arterial hypertension (PAH). The functional and molecular link between loss of BMPR2 in pulmonary artery smooth muscle cells (PASMC) and PAH pathogenesis warrants further investigation, as most investigations focus on BMPR2 in pulmonary artery endothelial cells. Our goal was to determine whether and how decreased BMPR2 is related to the abnormal phenotype of PASMC in PAH.MethodsSMC-specific Bmpr2-/- mice (BKOSMC) were created and compared to controls in room air, after 3 weeks of hypoxia as a second hit, and following 4 weeks of normoxic recovery. Echocardiography, right ventricular systolic pressure, and right ventricular hypertrophy were assessed as indices of pulmonary hypertension. Proliferation, contractility, gene and protein expression of PASMC from BKOSMC mice, human PASMC with BMPR2 reduced by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation were compared to controls, to investigate the phenotype and underlying mechanism.ResultsBKOSMC mice showed reduced hypoxia-induced vasoconstriction and persistent pulmonary hypertension following recovery from hypoxia, associated with sustained muscularization of distal pulmonary arteries. PASMC from mutant compared to control mice displayed reduced contractility at baseline and in response to angiotensin II, increased proliferation and apoptosis resistance. Human PASMC with reduced BMPR2 by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation showed a similar phenotype related to upregulation of pERK1/2 (phosphorylated extracellular signal related kinase 1/2)-pP38-pSMAD2/3 mediating elevation in ARRB2 (β-arrestin2), pAKT (phosphorylated protein kinase B) inactivation of GSK3-beta, CTNNB1 (β-catenin) nuclear translocation and reduction in RHOA (Ras homolog family member A) and RAC1 (Ras-related C3 botulinum toxin substrate 1). Decreasing ARRB2 in PASMC with reduced BMPR2 restored normal signaling, reversed impaired contractility and attenuated heightened proliferation and in mice with inducible loss of BMPR2 in SMC, decreasing ARRB2 prevented persistent pulmonary hypertension.ConclusionsAgents that neutralize the elevated ARRB2 resulting from loss of BMPR2 in PASMC could prevent or reverse the aberrant hypocontractile and hyperproliferative phenotype of these cells in PAH.
| S-EPMC10008520 | biostudies-literature
Project description:Pulmonary hypertension (PH) is one of the most devastating cardiovascular diseases worldwide and it draws much attention from numerous scientists. As an indispensable part of pulmonary artery, smooth muscle cells are worthy of being carefully investigated. To elucidate the pathogenesis of PH, several theories focusing on pulmonary artery smooth muscle cells (PASMC), such as hyperproliferation, resistance to apoptosis, and cancer theory, have been proposed and widely studied. Here, we tried to summarize the studies, concentrating on the role of PASMC in the development of PH, feasible molecular basis to intervene, and potential treatment to PH.
| S-EPMC7441461 | biostudies-literature
Project description:Pulmonary hypertension (PH) is a life‑threatening disease that often involves vascular remodeling. Although pulmonary arterial smooth muscle cells (PASMCs) are the primary participants in vascular remodeling, their biological role is not entirely clear. The present study analyzed the role of enhancer of zeste homolog 2 (EZH2) in vascular remodeling of PH by investigating the behavior of PASMCs. The expression levels of EZH2 in PASMCs in chronic thromboembolic pulmonary hypertension (CTEPH), a type of PH, were detected. The role of EZH2 in PASMC migration was investigated by wound‑healing assay following overexpression and knockdown. Functional enrichment analysis of the whole‑genome expression profiles of PASMCs with EZH2 overexpression was performed using an mRNA Human Gene Expression Microarray. Quantitative (q)PCR was performed to confirm the results of the microarray. EZH2 expression levels increased in CTEPH cell models. The overexpression of EZH2 enhanced PASMC migration compared with control conditions. Functional enrichment analysis of the differentially expressed genes following EZH2 overexpression indicated a strong link between EZH2 and the immune inflammatory response and oxidoreductase activity in PASMCs. mRNA expression levels of superoxide dismutase 3 were verified by qPCR. The results suggested that EZH2 was involved in the migration of PASMCs in PH, and may serve as a potential target for the treatment of PH.
| S-EPMC7751464 | biostudies-literature
Project description:Excess and ectopic smooth muscle cells (SMCs) are central to cardiovascular disease pathogenesis, but underlying mechanisms are poorly defined. For instance, pulmonary hypertension (PH) or elevated pulmonary artery blood pressure is a devastating disease with distal extension of smooth muscle to normally unmuscularized pulmonary arterioles. We identify novel SMC progenitors that are located at the pulmonary arteriole muscular-unmuscular border and express both SMC markers and the undifferentiated mesenchyme marker platelet-derived growth factor receptor-? (PDGFR-?). We term these cells "primed" because in hypoxia-induced PH, they express the pluripotency factor Kruppel-like factor 4 (KLF4), and in each arteriole, one of them migrates distally, dedifferentiates, and clonally expands, giving rise to the distal SMCs. Furthermore, hypoxia-induced expression of the ligand PDGF-B regulates primed cell KLF4 expression, and enhanced PDGF-B and KLF4 levels are required for distal arteriole muscularization and PH. Finally, in PH patients, KLF4 is markedly up-regulated in pulmonary arteriole smooth muscle, especially in proliferating SMCs. In sum, we have identified a pool of SMC progenitors that are critical for the pathogenesis of PH, and perhaps other vascular disorders, and therapeutic strategies targeting this cell type promise to have profound implications.
| S-EPMC4629985 | biostudies-literature
Project description:Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis is increased and how increased glycolysis contributes to pulmonary vascular remodeling in PAH.Objectives: To determine whether increased glycolysis is caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and how PFKFB3-driven glycolysis induces vascular remodeling in PAH.Methods: PFKFB3 levels were measured in pulmonary arteries of patients and animals with PAH. Lactate levels were assessed in lungs of animals with PAH and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacologic approaches were used to investigate the role of PFKFB3 in PAH.Measurements and Main Results: Lactate production was elevated in lungs of PAH rodents and in platelet-derived growth factor-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of patients and rodents with PAH, in PASMCs of patients with PAH, and in platelet-derived growth factor-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of extracellular signal-regulated kinase (ERK1/2) and calpain-2, and vascular remodeling in PAH rodent models, and reduced platelet-derived growth factor-induced phosphorylation/activation of ERK1/2 and calpain-2, collagen synthesis and proliferation of PASMCs. ERK1/2 inhibition attenuated phosphorylation/activation of calpain-2, and vascular remodeling in Sugen/hypoxia PAH rats, and reduced lactate-induced phosphorylation/activation of calpain-2, collagen synthesis, and proliferation of PASMCs. Calpain-2 inhibition reduced lactate-induced collagen synthesis and proliferation of PASMCs.Conclusions: Upregulated PFKFB3 mediates collagen synthesis and proliferation of PASMCs, contributing to vascular remodeling in PAH. The mechanism is through the elevation of glycolysis and lactate that results in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2.
| S-EPMC6727156 | biostudies-literature
Project description:Idiopathic pulmonary arterial hypertension (IPAH) is a disease with complex etiology. Currently, IPAH treatment is limited, and patients' prognosis is poor. This study aimed to explore new therapeutic targets in IPAH through bioinformatics. Two data sets (GSE113439 and GSE130391) meeting the requirements were obtained from the Gene Expression Omnibus (GEO) database. Then, differentially expressed genes (DEGs) were identified and analyzed by NetworkAnalyst platform. By enriching Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), we examined the function of DEGs. A protein-protein interaction (PPI) network was constructed to identify central genes using the CytoNCA plug-in. Finally, four central genes, ASPM, CENPE, NCAPG, and TOP2A, were screened out. We selected NCAPG for protein-level verification. We established an animal model of PAH and found that the expression of NCAPG was significantly increased in the lung tissue of PAH rats. In vitro experiments showed that the expression of NCAPG was significantly increased in proliferative pulmonary arterial smooth muscle cells (PASMCs). When NCAPG of PASMCs was knocked down, the cell proliferation was inhibited, which suggested that NCAPG was related to the proliferation of PASMCs. Therefore, these results may provide new therapeutic targets for IPAH.
| S-EPMC9570379 | biostudies-literature