Pathological vascular remodeling is a hallmark of various vascular diseases. Previous research has established the significance of andrographolide in maintaining gastric vascular homeostasis and its pivotal role in modulating endothelial barrier dysfunction, which leads to pathological vascular remodeling. Potassium dehydroandrographolide succinate (PDA), a derivative of andrographolide, has been clinically utilized in the treatment of inflammatory diseases precipitated by viral infections. This study investigates the potential of PDA in regulating pathological vascular remodeling. The effect of PDA on vascular remodeling was assessed through the complete ligation of the carotid artery in C57BL/6 mice. Experimental approaches, including rat aortic primary smooth muscle cell culture, flow cytometry, bromodeoxyuridine (BrdU) incorporation assay, Boyden chamber cell migration assay, spheroid sprouting assay, and Matrigel-based tube formation assay, were employed to evaluate the influence of PDA on the proliferation and motility of smooth muscle cells (SMCs). Molecular docking simulations and co-immunoprecipitation assays were conducted to examine protein interactions. The results revealed that PDA exacerbates vascular injury-induced pathological remodeling, as evidenced by enhanced neointima formation. PDA treatment significantly increased the proliferation and migration of SMCs. Further mechanistic studies disclosed that PDA upregulated myeloid differentiation factor 88 (MyD88) expression in SMCs and interacted with T-cadherin (CDH13). This interaction augmented proliferation, migration, and extracellular matrix deposition, culminating in pathological vascular remodeling. Our findings underscore the critical role of PDA in the regulation of pathological vascular remodeling, mediated through the MyD88/CDH13 signaling pathway.
Mice ; Rats ; Animals ; Myeloid Differentiation Factor 88/metabolism* ; Vascular Remodeling ; Cell Proliferation ; Vascular System Injuries/pathology* ; Carotid Artery Injuries/pathology* ; Molecular Docking Simulation ; Muscle, Smooth, Vascular ; Cell Movement ; Mice, Inbred C57BL ; Signal Transduction ; Succinates/pharmacology* ; Potassium/pharmacology* ; Cells, Cultured ; Diterpenes ; Cadherins

Vascular calcification is an active and complex pathological process regulated by several factors. Vascular calcification is closely related to the incidence and mortality of the cardiovascular disease, chronic kidney disease and other diseases, which affects multiple organs and systems, thus affecting people's health. Therefore, more and more attention is paid to vascular calcification. At present, the pathogenesis and clinical practice of vascular calcification have been continuously improved, which mainly includes calcium and phosphorus imbalance theory, vascular smooth muscle cell transdifferentiation theory, bone homeostasis imbalance theory, epigenetic regulation theory, inflammation theory, extracellular matrix theory, new cell fate theory and so on. However, there are still many unsolved problems. Since the occurrence and development of vascular calcification affect multiple organs and systems, this expert consensus gathered clinicians and basic research experts engaged in the study of vascular calcification in order to summarize the progress of various disciplines related to vascular calcification in recent years. The purpose of this consensus is to systematically summarize the latest research progress, treatment consensus and controversy of vascular calcification from the aspects of epidemiology, pathogenesis, prevention and treatment, so as to provide theoretical basis and clinical enlightenment for in-depth research in this field.
Humans ; Consensus ; Epigenesis, Genetic ; Vascular Calcification/pathology* ; Cardiovascular Diseases ; Myocytes, Smooth Muscle

Vascular calcification is the crucial factor of high cardiovascular disease morbidity and mortality in patients with chronic kidney disease (CKD), which causes a huge medical and economic burden. It is urgent to explore its pathogenesis and intervention methods. CKD-associated vascular calcification is an ectopic osteogenesis process actively regulated by multiple cells. Vascular smooth muscle cells (VSMCs) undergo osteogenic differentiation in a pro-calcification environment, and secrete matrix vesicles to form calcium and phosphorus crystal deposition sites, which are key events in the development of CKD-associated vascular calcification. This article reviews the new mechanism and technology of CKD-associated vascular calcification and discusses the role of the myokine Irisin in CKD-associated vascular calcification.
Humans ; Osteogenesis ; Renal Insufficiency, Chronic ; Vascular Calcification/pathology* ; Proteins ; Cardiovascular Diseases/complications* ; Disease Progression ; Myocytes, Smooth Muscle

OBJECTIVE: To investigate the effects of Bax inhibitor 1 (BI- 1) and optic atrophy protein 1 (OPA1) on vascular calcification (VC). METHODS: Mouse models of VC were established in ApoE-deficient (ApoE^-/-) diabetic mice by high-fat diet feeding for 12 weeks followed by intraperitoneal injections with N^ε-carboxymethyl-lysine for 16 weeks. ApoE^-/- mice (control group), ApoE^-/- diabetic mice (VC group), ApoE^-/- diabetic mice with BI-1 overexpression (VC + BI-1^TG group), and ApoE^-/- diabetic mice with BI-1 overexpression and OPA1 knockout (VC+BI-1^TG+OPA1^-/- group) were obtained for examination of the degree of aortic calcification using von Kossa staining. The changes in calcium content in the aorta were analyzed using ELISA. The expressions of Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP-2) were detected using immunohistochemistry, and the expression of cleaved caspase-3 was determined using Western blotting. Cultured mouse aortic smooth muscle cells were treated with 10 mmol/L β-glycerophosphate for 14 days to induce calcification, and the changes in BI-1 and OPA1 protein expressions were examined using Western blotting and cell apoptosis was detected using TUNEL staining. RESULTS: ApoE^-/- mice with VC showed significantly decreased expressions of BI-1 and OPA1 proteins in the aorta (P=0.0044) with obviously increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P= 0.0041). Overexpression of BI-1 significantly promoted OPA1 protein expression and reduced calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P=0.0006). OPA1 knockdown significantly increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 in the aorta (P=0.0007). CONCLUSION BI-1 inhibits VC possibly by promoting the expression of OPA1, reducing calcium deposition and inhibiting osteogenic differentiation and apoptosis of the vascular smooth muscle cells.
Animals ; Apolipoproteins E/metabolism* ; Calcium/metabolism* ; Caspase 3/metabolism* ; Cells, Cultured ; Core Binding Factor Alpha 1 Subunit/metabolism* ; Diabetes Mellitus, Experimental/pathology* ; GTP Phosphohydrolases/metabolism* ; Membrane Proteins/metabolism* ; Mice ; Mice, Knockout ; Muscle, Smooth, Vascular/pathology* ; Myocytes, Smooth Muscle/pathology* ; Optic Atrophy, Autosomal Dominant/pathology* ; Osteogenesis ; Vascular Calcification/pathology* ; bcl-2-Associated X Protein/metabolism*

Vascular smooth muscle cells (VSMC) are the main cellular component of vessel wall. The changes of VSMC functions including phenotypic transformation and apoptosis play a critical role in the pathogenesis of intracranial aneurysm (IA). Autophagy can participate in the regulation of vascular function by regulating cell function. In the initial stage of IA, the activation of autophagy can accelerate the phenotypic transformation of VSMC and inhibit VSMC apoptosis. With the progress of IA, the relationship between autophagy and apoptosis changes from antagonism to synergy or promotion, and a large number of apoptotic VSMC lead to the rupture of IA. In this review, we describe the role of autophagy regulating the function of VSMC in the occurrence, development and rupture of IA, for further understanding the pathogenesis of IA and finding molecular targets to prevent the formation and rupture of IA.
Autophagy ; Humans ; Intracranial Aneurysm ; pathology ; Muscle, Smooth, Vascular ; cytology ; Myocytes, Smooth Muscle ; cytology

Pulmonary arterial hypertension (PAH) is a clinical hemodynamic syndrome characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance leading to right heart failure and death. Vascular remodeling is the most prominent histopathological feature of PAH, which is regulated by many factors. Endoplasmic reticulum stress, calcium disorder and mitochondrial dysfunction are involved in the vascular cell proliferation and apoptosis by regulating intracellular calcium homeostasis and cellular metabolism. Epigenetic phenomenon such as DNA damage and abnormal expression of miRNA are also involved in the regulation of abnormal proliferation of vascular cells. Vascular cell phenotype switching including endothelial-mesenchymal transition and smooth muscle cell phenotype switching play an important role in abnormal proliferation of vascular cells. Vascular remodeling is produced by a variety of cells and molecular pathways, and aiming at multiple targets which is expected to find a new breakthrough in the treatment of PAH,and to improve abnormal vascular remodeling, delay or even reverse the progression of PAH.
Cell Proliferation ; Cells, Cultured ; Humans ; Hypertension, Pulmonary ; physiopathology ; MicroRNAs ; genetics ; Myocytes, Smooth Muscle ; pathology ; Pulmonary Artery ; pathology ; Vascular Remodeling ; genetics

Autophagy plays a crucial role in maintaining normal structure and vascular function in vivo. When stress-relevant stimuli are involved, the increases of autophagy can protect vascular smooth muscle cells, promote cell survival, and phenotype transformation, as well as reduce calcification. On the contrary, the decrease of autophagy can accelerate cell senescence, resulting in structural changes and dysfunction of vasomotor and vasodilation. However, excessive activation of autophagy can induce the damage of the healthy protein and essential organelles, and even lead to autophagic cell death, accelerating the progression of vascular disease. Thus, the precise targeting of autophagy opens a novel way for treatment of vascular diseases.
Autophagy ; physiology ; Cell Survival ; Cellular Senescence ; Disease Progression ; Humans ; Muscle, Smooth, Vascular ; cytology ; Myocytes, Smooth Muscle ; physiology ; Vascular Diseases ; pathology ; therapy

Osteoclast-like cells are known to inhibit arterial calcification. Receptor activator of NF-κB ligand (RANKL) is likely to act as an inducer of osteoclast-like cell differentiation. However, several studies have shown that RANKL promotes arterial calcification rather than inhibiting arterial calcification. The present study was conducted in order to investigate and elucidate this paradox. Firstly, RANKL was added into the media, and the monocyte precursor cells were cultured. Morphological observation and Tartrate resistant acid phosphatase (TRAP) staining were used to assess whether RANKL could induce the monocyte precursor cells to differentiate into osteoclast-like cells. During arterial calcification, in vivo and in vitro expression of RANKL and its inhibitor, osteoprotegerin (OPG), was detected by real-time PCR. The extent of osteoclast-like cell differentiation was also assessed. It was found RANKL could induce osteoclast-like cell differentiation. There was no in vivo or in vitro expression of osteoclast-like cells in the early stage of calcification. At that time, the ratio of RANKL to OPG was very low. In the late stage of calcification, a small amount of osteoclast-like cell expression coincided with a relatively high ratio of RANKL to OPG. According to the results, the ratio of RANKL to OPG was very low during most of the arterial calcification period. This made it possible for OPG to completely inhibit RANKL-induced osteoclast-like cell differentiation. This likely explains why RANKL had the ability to induce osteoclast-like cell differentiation but acted as a promoter of calcification instead.
Acid Phosphatase ; genetics ; metabolism ; Animals ; Aorta ; drug effects ; metabolism ; pathology ; Cell Differentiation ; Coculture Techniques ; Gene Expression Regulation ; Isoenzymes ; genetics ; metabolism ; Male ; Monocytes ; cytology ; drug effects ; metabolism ; Myocytes, Smooth Muscle ; drug effects ; metabolism ; pathology ; Osteoclasts ; drug effects ; metabolism ; pathology ; Osteoprotegerin ; genetics ; metabolism ; RANK Ligand ; genetics ; metabolism ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Tartrate-Resistant Acid Phosphatase ; Vascular Calcification ; genetics ; metabolism ; pathology

Intimal accumulation of smooth muscle cells contributes to the development and progression of atherosclerotic lesions and restenosis following endovascular procedures. Arterial smooth muscle cells display heterogeneous phenotypes in both physiological and pathological conditions. In response to injury, dedifferentiated or synthetic smooth muscle cells proliferate and migrate from the tunica media into the intima. As a consequence, smooth muscle cells in vascular lesions show a prevalent dedifferentiated phenotype compared to the contractile appearance of normal media smooth muscle cells. The discovery of abundant stem antigen-expressing cells in vascular lesions also rarely detected in the tunica media of normal adult vessels stimulated a great scientific debate concerning the possibility that proliferating vascular wall-resident stem cells accumulate into the neointima and contribute to the progression of lesions. Although several experimental studies support this hypothesis, others researchers suggest a positive effect of stem cells on plaque stabilization. So, the real contribute of vascular wall-resident stem cells to pathological vascular remodelling needs further investigation. This review will examine the evidence and the contribution of vascular wall-resident stem cells to arterial pathobiology, in order to address future investigations as potential therapeutic target to prevent the progression of vascular diseases.
Adult ; Endovascular Procedures ; Humans ; Myocytes, Smooth Muscle ; Neointima ; Pathology* ; Phenotype ; Stem Cells* ; Tunica Media ; Vascular Diseases

In women with preeclampsia (PE), endothelial cell (EC) dysfunction can lead to altered secretion of paracrine factors that induce peripheral vasoconstriction and proteinuria. This study examined the hypothesis that PE sera may directly or indirectly, through human umbilical vein ECs (HUVECs), stimulate phospholipase C-gamma1-1,4,5-trisphosphate (PLC-gamma1-IP3) signaling, thereby increasing protein kinase C-alpha (PKC-alpha) activity, collagen I expression and intracellular Ca2+ concentrations ([Ca2+]i) in human umbilical artery smooth muscle cells (HUASMCs). HUASMCs and HUVECs were cocultured with normal or PE sera before PLC-gamma1 silencing. Increased PLC-gamma1 and IP3 receptor (IP3R) phosphorylation was observed in cocultured HUASMCs stimulated with PE sera (P<0.05). In addition, PE serum significantly increased HUASMC viability and reduced their apoptosis (P<0.05); these effects were abrogated with PLC-gamma1 silencing. Compared with normal sera, PE sera increased [Ca2+]i in cocultured HUASMCs (P<0.05), which was inhibited by PLC-gamma1 and IP3R silencing. Finally, PE sera-induced PKC-alpha activity and collagen I expression was inhibited by PLC-gamma1 small interfering RNA (siRNA) (P<0.05). These results suggest that vasoactive substances in the PE serum may induce deposition in the extracellular matrix through the activation of PLC-gamma1, which may in turn result in thickening and hardening of the placental vascular wall, placental blood supply shortage, fetal hypoxia-ischemia and intrauterine growth retardation or intrauterine fetal death. PE sera increased [Ca2+]i and induced PKC-alpha activation and collagen I expression in cocultured HUASMCs via the PLC-gamma1 pathway.
Adult ; Apoptosis ; Calcium/*metabolism ; Cell Line ; Cell Survival ; Cells, Cultured ; Coculture Techniques ; Collagen Type I/analysis/*metabolism ; Female ; Human Umbilical Vein Endothelial Cells ; Humans ; Muscle, Smooth, Vascular/*cytology/metabolism ; Phospholipase C gamma/genetics/*metabolism ; Pre-Eclampsia/*blood/*metabolism/pathology ; Pregnancy ; Protein Kinase C-alpha/metabolism ; RNA Interference ; *Signal Transduction ; Young Adult