Phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs) is a key factor in pulmonary vascular remodeling. Inhibiting or reversing phenotypic transformation can inhibit pulmonary vascular remodeling and control the progression of hypoxic pulmonary hypertension. Recent studies have shown that hypoxia causes intracellular peroxide metabolism to induce oxidative stress, induces multi-pathway signal transduction, including those related to autophagy, endoplasmic reticulum stress and mitochondrial dysfunction, and also induces non-coding RNA regulation of cell marker protein expression, resulting in PASMCs phenotypic transformation. This article reviews recent research progress on mechanisms of hypoxia-induced phenotypic transformation of PASMCs, which may be helpful for finding targets to inhibit phenotypic transformation and to improve pulmonary vascular remodeling diseases such as hypoxia-induced pulmonary hypertension.
Humans ; Pulmonary Artery ; Hypertension, Pulmonary ; Vascular Remodeling/genetics* ; Hypoxia/genetics* ; Myocytes, Smooth Muscle ; Cell Proliferation/physiology* ; Cells, Cultured ; Cell Hypoxia/genetics*

OBJECTIVES: To study the effect of platelet-derived growth factor-BB (PDGF-BB) on pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension (HPH). METHODS: A total of 128 neonatal rats were randomly divided into four groups: PDGF-BB+HPH, HPH, PDGF-BB+normal oxygen, and normal oxygen (n=32 each). The rats in the PDGF-BB+HPH and PDGF-BB+normal oxygen groups were given an injection of 13 μL 6×10¹⁰ PFU/mL adenovirus with PDGF-BB genevia the caudal vein. After 24 hours of adenovirus transfection, the rats in the HPH and PDGF-BB+HPH groups were used to establish a neonatal rat model of HPH. Right ventricular systolic pressure (RVSP) was measured on days 3, 7, 14, and 21 of hypoxia. Hematoxylin-eosin staining was used to observe pulmonary vascular morphological changes under an optical microscope, and vascular remodeling parameters (MA% and MT%) were also measured. Immunohistochemistry was used to measure the expression levels of PDGF-BB and proliferating cell nuclear antigen (PCNA) in lung tissue. RESULTS: The rats in the PDGF-BB+HPH and HPH groups had a significantly higher RVSP than those of the same age in the normal oxygen group at each time point (P<0.05). The rats in the PDGF-BB+HPH group showed vascular remodeling on day 3 of hypoxia, while those in the HPH showed vascular remodeling on day 7 of hypoxia. On day 3 of hypoxia, the PDGF-BB+HPH group had significantly higher MA% and MT% than the HPH, PDGF-BB+normal oxygen, and normal oxygen groups (P<0.05). On days 7, 14, and 21 of hypoxia, the PDGF-BB+HPH and HPH groups had significantly higher MA% and MT% than the PDGF-BB+normal oxygen and normal oxygen groups (P<0.05). The PDGF-BB+HPH and HPH groups had significantly higher expression levels of PDGF-BB and PCNA than the normal oxygen group at all time points (P<0.05). On days 3, 7, and 14 of hypoxia, the PDGF-BB+HPH group had significantly higher expression levels of PDGF-BB and PCNA than the HPH group (P<0.05), while the PDGF-BB+normal oxygen group had significantly higher expression levels of PDGF-BB and PCNA than the normal oxygen group (P<0.05). CONCLUSIONS Exogenous administration of PDGF-BB in neonatal rats with HPH may upregulate the expression of PCNA, promote pulmonary vascular remodeling, and increase pulmonary artery pressure.
Rats ; Animals ; Hypertension, Pulmonary ; Becaplermin ; Animals, Newborn ; Proliferating Cell Nuclear Antigen ; Vascular Remodeling ; Pulmonary Artery/metabolism* ; Hypoxia ; Oxygen ; Cell Proliferation ; Myocytes, Smooth Muscle/metabolism*

OBJECTIVE: To investigate the role of myelin and lymphocyte protein (MAL) in pulmonary hypertension (PAH). METHODS: Blood samples were collected from 50 patients with PAH (PAH group) and 50 healthy individuals for detection of plasma MAL expression using ELISA.According to the echocardiographic findings, the patients were divided into moderate/severe group (n=18) and mild group (n=32), and the correlation between MAL protein level and the severity of PAH was analyzed.In a pulmonary artery smooth muscle cell model of PAH with hypoxia-induced abnormal proliferation, the effects of mal gene knockdown and overexpression on cell growth, proliferation and starvation-induced apoptosis were observed; the changes in NK-κB signaling pathway in the transfected cells were detected to explore the molecular mechanism by which MAL regulates PAMSC proliferation and apoptosis. RESULTS: The plasma level of MAL was significantly higher in patients with PAH than in healthy individuals (P < 0.05), and the patients with moderate/severe PAH had significantly higher MAL level than those with mild PAH (P < 0.001).In PAMSCs, exposure to hypoxia significantly increased the mRNA and protein expression levels of MAL (P < 0.05), and MAL knockdown obviously inhibited hypoxia-induced proliferation and promoted starvation-induced apoptosis of the PAMSCs (P < 0.05).Knocking down mal significantly inhibited the activation of NK-κB signaling pathway that participated in regulation of PAMSC proliferation (P < 0.05). CONCLUSION The plasma level of MAL is elevated in PAH patients in positive correlation with the disease severity.MAL knockdown inhibits abnormal proliferation and promotes apoptosis of PAMSCs by targeted inhibition of the NF-κB signaling pathway to improve vascular remodeling in PAH.
Humans ; Pulmonary Artery ; Hypertension, Pulmonary ; Myelin Sheath/metabolism* ; Apoptosis ; Myocytes, Smooth Muscle ; Vascular Remodeling/genetics* ; Cell Proliferation ; Hypoxia/metabolism* ; Lymphocytes

OBJECTIVE: To study the role of vascular endothelial growth factor-A (VEGF-A) in pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension (HPH) by regulating survivin (SVV). METHODS: A total of 96 neonatal rats were randomly divided into three groups: HPH+VEGF-A group, HPH group, and control group. Each group was further randomly divided into 3-, 7-, 10-, and 14-day subgroups ( RESULTS: The HPH group had a significantly higher mean RVSP than the control and HPH+VEGF-A groups at each time point ( CONCLUSIONS Prophylactic intratracheal administration of exogenous VEGF-A in neonatal rats with HPH can inhibit pulmonary vascular remodeling and reduce pulmonary arterial pressure by upregulating the expression of SVV in the early stage of hypoxia. This provides a basis for the interventional treatment of pulmonary vascular remodeling in neonatal HPH.
Animals ; Animals, Newborn ; Hypertension, Pulmonary/etiology* ; Hypoxia ; Pulmonary Artery ; Rats ; Rats, Wistar ; Vascular Endothelial Growth Factor A ; Vascular Remodeling

Pulmonary hypertension is a kind of progressive pulmonary vascular diseases in which there is excessive vasoconstriction and abnormal pulmonary vascular remodeling, and then a gradual increase in pulmonary arterial pressure, and it eventually leads to right ventricular failure and even death. The pathogenesis of pulmonary hypertension is still uncertain, but some studies suggest that Hippo pathway or some components of the Hippo pathway may be involved in the progress of pulmonary hypertension. In this review, we describe the mechanism of the Hippo pathway or some components of the Hippo pathway in the progress of pulmonary hypertension.
Pulmonary hypertension ; Hippo pathway ; pulmonary vascular remodeling ; review

The occurrence and development of pulmonary arterial hypertension (PAH) is closely related to the genetic mutation of bone morphogenetic protein receptor type II (BMPRII) encoding gene and the inflammatory response mediated by nuclear factor κB (NF-κB) pathway. This paper was aimed to investigate the effect of NF-κB pathway inhibitors on lipopolysaccharide (LPS)-induced pulmonary artery endothelial cell injury. Human pulmonary artery endothelial cells were treated with 1 μg/mL of LPS. The expression levels of BMPRII and interleukin-8 (IL-8) were detected by Western blot and qPCR. The rat PAH model was established by intraperitoneal (i.p.) injection of monocrotaline (MCT). The expression levels of BMPRII and IL-8 in pulmonary artery endothelial cells were detected by immunofluorescence staining. Cardiac hemodynamic changes and pulmonary vascular remodeling were detected in the MCT-PAH model rats. The results showed that LPS caused down-regulation of BMPRII expression and up-regulation of IL-8 expression in human pulmonary artery endothelial cells. NF-κB inhibitor BAY11-7082 (10 μmol/L) reversed the effect of LPS. In the pulmonary artery endothelial cells of MCT-PAH model, BMPRII expression was down-regulated, IL-8 expression was up-regulated, weight ratio of right ventricle to left ventricle plus septum [RV/(LV+S)] and right ventricular systolic pressure (RVSP) were significantly increased, cardiac output (CO) and tricuspid annular plane systolic excursion (TAPSE) were significantly reduced, and pulmonary vessel wall was significantly thickened. BAY11-7082 (5 mg/kg, i.p., 21 consecutive days) reversed the above changes in the MCT-PAH model rats. These results suggest that LPS down-regulates the expression level of BMPRII through NF-κB signaling pathway, promoting the occurrence and development of PAH. Therefore, the NF-κB pathway can be used as a potential therapeutic target for PAH.
Animals ; Bone Morphogenetic Protein Receptors, Type II ; Down-Regulation ; Endothelial Cells/metabolism* ; Humans ; Hypertension, Pulmonary/drug therapy* ; Lipopolysaccharides ; NF-kappa B/metabolism* ; Rats ; Rats, Sprague-Dawley ; Vascular Remodeling

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

OBJECTIVE: To investigate the effects of apple polyphenols on pulmonary vascular remodeling in rats with pulmonary arterial hypertension and its mechanism. METHODS: Rats were randomly divided into 4 groups:control (Con) group, monocrotaline (MCT) group, apple polyphenol (APP) group,monocrotaline + apple polyphenol (MCT+APP) group. In Con group, rats received a subcutaneous injection of physical saline. In APP group, rats received intraperitoneal injection of 20 mg/kg APP, every other day. In MCT group, rats received a single subcutaneous injection of MCT(60 mg/kg). In MCT+APP group, rats received subcutaneous injection of 60 mg/kg MCT followed by an intraperitoneal injection of 20 mg/kg APP every other day. All the disposal lasted 3 weeks. Then the PAH-relevant indicators, such as mean pulmonary artery pressure(mPAP), pulmonary vascular resistance(PVR), right ventricular hypertrophy index (RVHI) ,wall thickness (WT%) and wall area (WA%) were tested. After that, the inflammatory pathway related indicators, such as interleukin1(IL-1),interleukin1(IL-6), tumor necrosis factor α(TNF-α), cyclooxygenase 2(COX-2) and myeloperoxidase(MPO) in pulmonary tissue and free intracellular Ca in pulmonary smooth muscle cell(PASMC), content of eNOS and NO in endothelial cells were determined. RESULTS: Compared with the control group, the levels of mPAP, PVR, RVHI, WA%, WT%, and IL-1, IL-6, TNF-α, COX-2, MPO in tissue and the expression of Ca in PASMC of MCT group were increased significantly, while the contents of eNOS and NO in endothelial cells were decreased significantly (P＜0.05). Compared with the MCT group, the apple polyphenol treatment could improve the above mentioned situation, and the COX-2 and Ca indicators of the apple polyphenol treatment group were decreased significantly (P＜0.05). CONCLUSION MCT can increase COX-2 expression and intracellular Ca in pulmonary artery smooth muscle cells, decrease the contents of eNOS and NO in endothelial cells, while apple polyphenols can significantly inhibit these effects.
Animals ; Calcium ; metabolism ; Cyclooxygenase 2 ; metabolism ; Cytokines ; metabolism ; Malus ; chemistry ; Monocrotaline ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type III ; metabolism ; Polyphenols ; pharmacology ; Pulmonary Artery ; drug effects ; pathology ; Random Allocation ; Rats ; Vascular Remodeling ; drug effects

Angiotensin-(1-9) [Ang-(1-9)], generated from Ang I by Ang II converting enzyme 2, has been reported to have protective effects on cardiac and vascular remodeling. However, there is no report about the effect of Ang-(1-9) on pulmonary hypertension. The aim of the present study is to investigate whether Ang-(1-9) improves pulmonary vascular remodeling in monocrotaline (MCT)-induced pulmonary hypertensive rats. Sprague-Dawley rats received Ang-(1-9) (576 µg/kg/day) or saline via osmotic mini-pumps for 3 weeks. Three days after implantation of osmotic mini-pumps, 50 mg/kg MCT or vehicle were subcutaneously injected. MCT caused increases in right ventricular weight and systolic pressure, which were reduced by co-administration of Ang-(1-9). Ang-(1-9) also attenuated endothelial damage and medial hypertrophy of pulmonary arterioles as well as pulmonary fibrosis induced by MCT. The protective effects of Ang-(1-9) against pulmonary hypertension were inhibited by Ang type 2 receptor (AT₂R) blocker, but not by Mas receptor blocker. Additionally, the levels of LDH and inflammatory cytokines, such as TNF-α, MCP-1, IL-1β, and IL-6, in plasma were lower in Ang-(1-9) co-treated MCT group than in vehicle-treated MCT group. Changes in expressions of apoptosis-related proteins such as Bax, Bcl-2, Caspase-3 and -9 in the lung tissue of MCT rats were attenuated by the treatment with Ang-(1-9). These results indicate that Ang-(1-9) improves MCT-induced pulmonary hypertension by decreasing apoptosis and inflammatory reaction via AT₂R.
Angiotensins* ; Animals ; Apoptosis ; Arterioles ; Blood Pressure ; Caspase 3 ; Cytokines ; Hypertension* ; Hypertension, Pulmonary ; Hypertrophy ; Interleukin-6 ; Lung ; Monocrotaline ; Plasma ; Pulmonary Fibrosis ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 2 ; Vascular Remodeling

Hemoptysis is a common complication of pulmonary tuberculosis. Most of the cases of hemoptysis originate from hypertrophied bronchial arteries. Also, diabetes induces pulmonary vascular abnormalities such as endothelial dysfunction, inflammatory infiltration and pulmonary vascular remodeling. A 27-year-old male, with diabetes and a history of tuberculosis, underwent the procedure of pars plana vitrectomy under general anesthesia. After an uneventful intra-operative period, he had hemoptysis prior to extubation. Emergency fiberoptic bronchscopy showed blood plugs and spotted fresh blood at the right upper lobar bronchus. After successful embolization of the bronchial artery, the patient made a recovery and was discharged without experiencing any complication. Predisposing factors of hemoptysis in this case are presumed to be tuberculosis and diabetes. The bleeding might had been caused by the rupture of a weakened artery within the cavity in the right upper lobe, through expansion of the lung during manual ventilation by positive pressure.
Adult ; Anesthesia, General* ; Arteries ; Bronchi ; Bronchial Arteries ; Causality ; Diabetes Mellitus ; Emergencies ; Hemoptysis* ; Hemorrhage ; Humans ; Lung ; Male ; Rupture ; Tuberculosis* ; Tuberculosis, Pulmonary ; Vascular Remodeling ; Ventilation ; Vitrectomy