Vascular Homeostasis Research Articles

ENOS Glu298Asp (rs1799983) and AGT Met235Thr (rs699) polymorphisms in adverse cardiometabolic phenotypes: A study among Bhil tribal population of India

BackgroundCardiometabolic adversities constitute an enormous public health challenge. Along with lifestyle/socio-cultural determinants, disease outcome is modulated by genetic variants as well. Genetic polymorphisms like eNOS Glu298Asp (rs1799983) and AGT Met235Thr (rs699) have been identified as significant contributors to cardiometabolic phenotypes (obesity, hypertension and dyslipidemia) due to their role in vascular homeostasis, endothelial function, cardiac performance, etc. However, the association of these two genetic polymorphisms with cardiometabolic phenotypes among Indian Bhil tribal population have not yet been determined. MethodsThis was a cross-sectional study conducted among Bhil tribal population from India. The study recruited 297 participants aged 25–75 years through door-to-door household survey. Data on demographic and lifestyle variables were collected using a pre-tested modified interview schedule. Anthropometric (height, weight, waist circumference and hip circumference) and physiological (systolic and diastolic blood pressure) parameters were measured to define obesity and hypertension. Fasting blood samples were collected and serum was separated for lipid profiling (TC, TG, HDL-C, LDL-C and VLDL-C) and DNA was extracted from whole blood for genetic analysis (PCR-RFLP). Multivariable logistic regression was employed to identify association of genetic polymorphisms with cardiometabolic phenotypes. ResultsThe frequency of GG, GT and TT genotypes of eNOS rs1799983 were 52.86%, 45.45% and 1.68%, respectively and 0.24 minor allele frequency (MAF). The frequency of TT, TC and CC genotypes of AGT rs699 were 37.71%, 41.41% and 20.88%, respectively and 0.42 MAF. GT genotype and T allele (GT + TT genotypes) of rs1799983 were inversely associated with high WC, prehypertension, low HDL-C, and high LDL-C (all adjusted OR values <1 and p < 0.05). Conversely, TC and C allele (TC + CC genotypes) of rs699 were significantly associated with dyslipidemia, specifically high TC, TG and VLDL-C (all adjusted OR values >1.6 and p < 0.05). Also, individuals with the combination of high TC and TC genotype or C allele of rs699 appeared to have survival disadvantage at older age. ConclusionWith high frequency of AGT rs699 mutant C allele and significant association with dyslipidemia, our study suggests screening of candidate gene polymorphisms for cardiometabolic diseases among tribal populations to identify risk genotypes or alleles, which may pave way for future pharmacogenetic therapy and precision medicine.

Molecular and Cellular Aspects of the Endothelial-Mesenchymal Transition in Cardiovascular Diseases

Endothelial cells (ECs), which form the inner surface of the blood vessels, contact the blood, withstand mechanical pressure, and demonstrate heterogeneous reactions to exogenous and endogenous stimuli. ECs have unique properties in accordance with their niches and play an important role in regulating vascular homeostasis. Endothelial cells may undergo a dynamic phenotypic switch in terms of its heterogeneity, which may lead to endothelial dysfunction and a number of associated pathologies. Endothelial-mesenchymal transition (EndMT) is one of the possible molecular and cellular mechanisms of this kind. EndMT is characterized by phenotypic changes in ECs through which endothelial cells acquire new properties, i.e., start producing mesenchymal markers such as alpha-SMA and vimentin, change morphology, and become able to migrate. EndMT is a complex biological process that can be induced by inflammation, hypoxia, or oxidative stress and be involved in pathogenesis of cardiovascular disease. This review describes the key markers, inhibitors, and inducers of endothelial-mesenchymal transition and overall state-of-the-art of EndMT in cardiovascular diseases.

Role of c-Src and reactive oxygen species in cardiovascular diseases.

Oxidative stress, caused by the over production of oxidants or inactivity of antioxidants, can modulate the redox state of several target proteins such as tyrosine kinases, mitogen-activated protein kinases and tyrosine phosphatases. c-Src is one such non-receptor tyrosine kinase which activates NADPH oxidases (Noxs) in response to various growth factors and shear stress. Interaction between c-Src and Noxs is influenced by cell type and primary messengers such as angiotensin II, which binds to G-protein coupled receptor and activates the intracellular signaling cascade. c-Src stimulated activation of Noxs results in elevated release of intracellular and extracellular reactive oxygen species (ROS). These ROS species disturb vascular homeostasis and cause cardiac hypertrophy, coronary artery disease, atherosclerosis and hypertension. Interaction between c-Src and ROS in the pathobiology of cardiac fibrosis is hypothesized to be influenced by cell type and stimuli. c-Src and ROS have a bidirectional relationship, thus increased ROS levels due to c-Src mediated activation of Noxs can further activate c-Src by promoting the oxidation and sulfenylation of critical cysteine residues. This review highlights the role of c-Src and ROS in mediating downstream signaling pathways underlying cardiovascular diseases. Furthermore, due to the central role of c-Src in activation of various signaling proteins involved in differentiation, migration, proliferation, and cytoskeletal reorganization of vascular cells, it is presented as therapeutic target for treating cardiovascular diseases except cardiac fibrosis.

Homeostatic, Non-Canonical Role of Macrophage Elastase in Vascular Integrity.

Matrix metalloproteinase (MMP)-12 is highly expressed in abdominal aortic aneurysms and its elastolytic function has been implicated in the pathogenesis. This concept is challenged, however, by conflicting data. Here, we sought to revisit the role of MMP-12 in abdominal aortic aneurysm. Apoe-/- and Mmp12-/-/Apoe-/- mice were infused with Ang II (angiotensin). Expression of neutrophil extracellular traps (NETs) markers and complement component 3 (C3) levels were evaluated by immunostaining in aortas of surviving animals. Plasma complement components were analyzed by immunoassay. The effects of a complement inhibitor, IgG-FH1-5 (factor H-immunoglobulin G), and macrophage-specific MMP-12 deficiency on adverse aortic remodeling and death from rupture in Ang II-infused mice were determined. Unexpectedly, death from aortic rupture was significantly higher in Mmp12-/-/Apoe-/- mice. This associated with more neutrophils, citrullinated histone H3 and neutrophil elastase, markers of NETs, and C3 levels in Mmp12-/- aortas. These findings were recapitulated in additional models of abdominal aortic aneurysm. MMP-12 deficiency also led to more pronounced elastic laminae degradation and reduced collagen integrity. Higher plasma C5a in Mmp12-/- mice pointed to complement overactivation. Treatment with IgG-FH1-5 decreased aortic wall NETosis and reduced adverse aortic remodeling and death from rupture in Ang II-infused Mmp12-/- mice. Finally, macrophage-specific MMP-12 deficiency recapitulated the effects of global MMP-12 deficiency on complement deposition and NETosis, as well as adverse aortic remodeling and death from rupture in Ang II-infused mice. An MMP-12 deficiency/complement activation/NETosis pathway compromises aortic integrity, which predisposes to adverse vascular remodeling and abdominal aortic aneurysm rupture. Considering these new findings, the role of macrophage MMP-12 in vascular homeostasis demands re-evaluation of MMP-12 function in diverse settings.

Endothelial Dysfunction Syndromes after Allogeneic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only therapy with a curative potential for a variety of malignant and non-malignant diseases. The major limitation of the procedure is the significant morbidity and mortality mainly associated with the development of graft versus host disease (GVHD) as well as with a series of complications related to endothelial injury, such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), transplant-associated thrombotic microangiopathy (TA-TMA), etc. Endothelial cells (ECs) are key players in the maintenance of vascular homeostasis and during allo-HSCT are confronted by multiple challenges, such as the toxicity from conditioning, the administration of calcineurin inhibitors, the immunosuppression associated infections, and the donor alloreactivity against host tissues. The early diagnosis of endothelial dysfunction syndromes is of paramount importance for the development of effective prophylactic and therapeutic strategies. There is an urgent need for the better understanding of the pathogenetic mechanisms as well as for the identification of novel biomarkers for the early diagnosis of endothelial damage. This review summarizes the current knowledge on the biology of the endothelial dysfunction syndromes after allo-HSCT, along with the respective therapeutic approaches, and discusses the strengths and weaknesses of possible biomarkers of endothelial damage and dysfunction.

The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression.

Fibrotic diseases, such as systemic sclerosis (SSc), idiopathic pulmonary fibrosis, renal fibrosis and liver cirrhosis are characterized by tissue overgrowth due to excessive extracellular matrix (ECM) deposition. Fibrosis progression is caused by ECM overproduction and the inhibition of ECM degradation due to several events, including inflammation, vascular endothelial dysfunction, and immune abnormalities. Recently, it has been reported that urokinase plasminogen activator (uPA) and its receptor (uPAR), known to be fibrinolytic factors, orchestrate the inflammatory response, vascular homeostasis, and immune homeostasis system. The uPA/uPAR system may show promise as a potential therapeutic target for fibrotic diseases. This review considers the role of the uPA/uPAR system in the progression of fibrotic diseases.

Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis.

Homocysteine (Hcy) is an intermediate amino acid formed during the conversion from methionine to cysteine. When the fasting plasma Hcy level is higher than 15 μmol/L, it is considered as hyperhomocysteinemia (HHcy). The vascular endothelium is an important barrier to vascular homeostasis, and its impairment is the initiation of atherosclerosis (AS). HHcy is an important risk factor for AS, which can promote the development of AS and the occurrence of cardiovascular events, and Hcy damage to the endothelium is considered to play a very important role. However, the mechanism by which Hcy damages the endothelium is still not fully understood. This review summarizes the mechanism of Hcy-induced endothelial injury and the treatment methods to alleviate the Hcy induced endothelial dysfunction, in order to provide new thoughts for the diagnosis and treatment of Hcy-induced endothelial injury and subsequent AS-related diseases.

Deficiency of thrombospondin-2 alleviates intimal hyperplasia in mice by modulating vascular smooth muscle cell proliferation and migration.

Thrombospondin-2 (Tsp2), a glycoprotein in the extracellular matrix, plays a critical role in the maintenance of vascular homeostasis. However, its role in the pathogenesis of cardiovascular disorders such as intimal hyperplasia is not fully elucidated. This study, therefore, aims to explore the effect of Tsp2 on intimal hyperplasia and its associated underlying mechanisms. Intimal hyperplasia (IH) was established using a modified wire-mediated femoral artery injury model. Immunofluorescence and qPCR identified upregulated Tsp2 expression in the injured femoral artery compared with the uninjured femoral artery. Similarly, TSP2 expression was also increased in human samples from the atherosclerotic femoral artery and colocalized with vascular smooth muscle cells (VSMCs). Compared with the wild-type littermates, Tsp2 knockout mice displayed a mitigated IH in the injured femoral artery, as demonstrated by a decreased neointimal area and intimal/median ratio. Primary mouse VSMCs were cultured to explore the mechanism by which Tsp2 influenced IH in vitro. PDGF-stimulated VSMCs presented an elevated Tsp2 expression and enhanced migration and proliferation. However, Tsp2 knockdown by siRNA blocked the increased migration and proliferation of VSMCs. Further analysis identified an association between Notch3 and IH when the intracellular domain of Notch3 (Nicd3) was upregulated in PDGF-stimulated VSMCs and femoral arteries with IH in human tissues. Along with the overexpression and downregulation of Tsp2, the Nicd3 expression was also up and downregulated accordingly. Tsp2 was associated with IH and may serve as a therapeutic target for IH. Downregulation of Tsp2 could mitigate the progression of IH by modulating the proliferation and migration of VSMCs.

Targeting soluble epoxide hydrolase promotes osteogenic-angiogenic coupling via activating SLIT3/HIF-1α signalling pathway.

Type H vessels have recently been identified to modulate osteogenesis. Epoxyeicostrioleic acids (EETs) have an essential contribution to vascular homeostasis. However, whether increased EETs with soluble epoxide hydrolase (sEH) inhibitor TPPU enhance the coupling of angiogenesis and osteogenesis remains largely unknown. The effects of TPPU on cross-talk between co-cultured human umbilical vein endothelial cells (HUVECs) and human dental pulp stem cells (hDPSCs), and on long bone growth and calvarial defect repair in mice were investigated in vitro and in vivo. TPPU enhanced osteogenic differentiation of co-cultured HUVECs and hDPSCs in vitro and increased type H vessels, and long bone growth and bone repair of calvarial defect. Mechanistically, TPPU promoted cell proliferation and angiogenesis, reclined cell apoptosis, and significantly increased CD31hi EMCNhi endothelial cells (ECs) and SLIT3 and HIF-1α expression levels in co-cultured HUVECs and hDPSCs. Knockdown of Slit3 in hDPSCs or Hif-1α in HUVECs impaired the formation of CD31hi EMCNhi ECs and reversed TPPU-induced osteogenesis. We defined a previously unidentified effect of TPPU coupling angiogenesis and osteogenesis. TPPU induced type H vessels by upregulating the expression of hDPSCs-derived SLIT3, which resulted in the activation of ROBO1/YAP1/HIF-1α signalling pathway in ECs. Targeting metabolic pathways of EETs represents a new strategy to couple osteogenesis and angiogenesis, sEH is a promising therapeutic target for bone regeneration and repair.

Effects of Salvia miltiorrhiza active compounds on placenta-mediated pregnancy complications.

Placenta-mediated pregnancy complications (PMPCs), including preeclampsia (PE), fetal growth restriction (FGR), and recurrent spontaneous abortion (RSA), occur in approximately 5% of pregnancies and are caused by abnormal placenta development. The development of effective therapies for PMPCs is still challenging due to the complicated pathogenesis, such as disrupted vascular homeostasis and subsequent abnormal placentation. Synthetic drugs have been recommended for treating PMPCs; however, they tend to cause adverse reactions in the mother and fetus. Salvia miltiorrhiza (S. miltiorrhiza) has potential effects on PMPCs owing to its advantages in treating cardiovascular disorders. S. miltiorrhiza and its active compounds could attenuate the symptoms of PMPCs through anticoagulation, vasodilation, antioxidation, and endothelial protection. Thus, in this review, we summarize the literature and provide comprehensive insights on S. miltiorrhiza and its phytochemical constituents, pharmacological activities, and on PMPCs, which would be valuable to explore promising drugs.

Red blood cells from endothelial nitric oxide synthase-deficient mice induce vascular dysfunction involving oxidative stress and endothelial arginase I

Background & aimsNitric oxide bioactivity (NO) from endothelial NO synthase (eNOS) importantly contributes to the maintenance of vascular homeostasis, and reduced eNOS activity has been associated with cardiovascular disease. Emerging evidence suggests interaction(s) between red blood cells (RBCs) and the endothelium in vascular control; however, the specific role of RBC eNOS is less clear. We aimed to investigate the hypothesis that a lack of RBC eNOS induces endothelial dysfunction. Methods & ResultsRBCs from global eNOS knockout (KO) and wildtype (WT) mice were co-incubated ex vivo overnight with healthy mouse aortic rings, followed by functional and mechanistic analyses of endothelium-dependent and independent relaxations. RBCs from eNOS KO mice induced endothelial dysfunction and vascular oxidative stress, whereas WT RBC did not. No differences were observed for endothelium-independent relaxations. This eNOS KO RBC-induced endothelial dysfunctional phenotype was prevented by concomitant co-incubation with reactive oxygen species scavenger (TEMPOL), arginase inhibitor (nor-NOHA), NO donor (detaNONOate) and NADPH oxidase 4 (NOX4) inhibitor. Moreover, vessels from endothelial cell-specific arginase 1 KO mice were resistant to eNOS KO-RBC-induced endothelial dysfunction. Finally, in mice aortae co-incubated with RBCs from women with preeclampsia, we observed a significant reduction in endothelial function compared to when using RBCs from healthy pregnant women or from women with uncomplicated gestational hypertension. ConclusionsRBCs from mice lacking eNOS, and patients with preeclampsia, induce endothelial dysfunction in adjacent blood vessels. Thus, RBC-derived NO bioactivity acts to prevent induction of vascular oxidative stress occurring via RBC NOX4-derived ROS in a vascular arginase-dependent manner. Our data highlight the intrinsic protective role of RBC-derived NO bioactivity in preventing the damaging potential of RBCs. This provides novel insight into the functional relationship between RBCs and the vasculature in health and cardiovascular disease, including preeclampsia.

Oxidative stress-induced MMP- and γ-secretase-dependent VE-cadherin processing is modulated by the proteasome and BMP9/10

Classical cadherins, including vascular endothelial (VE)-cadherin, are targeted by matrix metalloproteinases (MMPs) and γ-secretase during adherens junction (AJ) disassembly, a mechanism that might have relevance for endothelial cell (EC) integrity and vascular homeostasis. Here, we show that oxidative stress triggered by H2O2 exposure induced efficient VE-cadherin proteolysis by MMPs and γ-secretase in human umbilical endothelial cells (HUVECs). The cytoplasmic domain of VE-cadherin produced by γ-secretase, VE-Cad/CTF2—a fragment that has eluded identification so far—could readily be detected after H2O2 treatment. VE-Cad/CTF2, released into the cytosol, was tightly regulated by proteasomal degradation and was sequentially produced from an ADAM10/17-generated C-terminal fragment, VE-Cad/CTF1. Interestingly, BMP9 and BMP10, two circulating ligands critically involved in vascular maintenance, significantly reduced VE-Cad/CTF2 levels during H2O2 challenge, as well as mitigated H2O2-mediated actin cytoskeleton disassembly during VE-cadherin processing. Notably, BMP9/10 pretreatments efficiently reduced apoptosis induced by H2O2, favoring endothelial cell recovery. Thus, oxidative stress is a trigger of MMP- and γ-secretase-mediated endoproteolysis of VE-cadherin and AJ disassembly from the cytoskeleton in ECs, a mechanism that is negatively controlled by the EC quiescence factors, BMP9 and BMP10.

The role of pyroptosis in endothelial dysfunction induced by diseases

Most organs in the body rely on blood flow, and vesicular damage is the leading cause of injury in multiple organs. The endothelium, as the barriers of vessels, play a critical role in ensuring vascular homeostasis and angiogenesis. The rapid development of risk factors in endothelial injuries has been seen in the past decade, such as smoking, infectious, and diabetes mellites. Pyroptotic endothelium is an inflammatory mode of governed endothelial cell death that depend on the metabolic disorder and severe infectious such as atherosclerosis, and sepsis-related acute lung injury, respectively. Pyroptotic endothelial cells need GSDMD cleaved into N- and C-terminal by caspase1, and the cytokines are released by a pore constructed by the N-terminal of GSDMD in the membrane of ECs, finally resulting in severe inflammation and pyroptotic cell death. This review will focus on the patho-physiological and pharmacological pathways of pyroptotic endothelial metabolism in diseases. Overall, this review indicates that pyroptosis is a significant risk factor in diseases and a potential drug target in related diseases.

The role of pyroptosis in endothelial dysfunction induced by diseases.

Most organs in the body rely on blood flow, and vesicular damage is the leading cause of injury in multiple organs. The endothelium, as the barriers of vessels, play a critical role in ensuring vascular homeostasis and angiogenesis. The rapid development of risk factors in endothelial injuries has been seen in the past decade, such as smoking, infectious, and diabetes mellites. Pyroptotic endothelium is an inflammatory mode of governed endothelial cell death that depend on the metabolic disorder and severe infectious such as atherosclerosis, and sepsis-related acute lung injury, respectively. Pyroptotic endothelial cells need GSDMD cleaved into N- and C-terminal by caspase1, and the cytokines are released by a pore constructed by the N-terminal of GSDMD in the membrane of ECs, finally resulting in severe inflammation and pyroptotic cell death. This review will focus on the patho-physiological and pharmacological pathways of pyroptotic endothelial metabolism in diseases. Overall, this review indicates that pyroptosis is a significant risk factor in diseases and a potential drug target in related diseases.

Meet the First Authors.

Meet the First Authors.

Semaphorin 7A promotes human vascular smooth muscle cell proliferation and migration through the β-catenin signaling pathway

Background: Vascular smooth muscle cells (VSMCs) undergo a conversion from a contractile phenotype to a proliferative synthetic phenotype, contributing to the pathogenesis of cardiovascular diseases. Semaphorin 7A (SEMA7A) is a glycosylphosphatidylinositol-anchored membrane protein that plays an important role in vascular homeostasis by regulating endothelial cell behaviors. However, the expression and role of SEMA7A in VSMCs remain unclear.Methods: In this study, we screened for VSMC-regulating genes in publicly available datasets and analyzed the expression of SEMA7A in human coronary artery smooth muscle cells (hCASMCs) treated with platelet-derived growth factor-BB (PDGF-BB). The effects of SEMA7A overexpression and knockdown on hCASMC proliferation and migration were examined. The signaling pathways involved in the action of SEMA7A in hCASMCs were determined.Results: Bioinformatic analysis showed that SEMA7A was significantly dysregulated in VSMCs treated with oxidized low-density lipoprotein or overexpressing progerin, a pro-atherogenic gene. The PDGF-BB stimulation led to a concentration- and time-dependent induction of SEMA7A. Depletion of SEMA7A attenuated PDGF-BB-induced hCASMC proliferation and migration. Conversely, overexpression of SEMA7A enhanced hCASMC proliferation and migration. Mechanistically, SEMA7A stimulated the activation of the β-catenin pathway and upregulated c-Myc, CCND1, and MMP7. Knockdown of β-catenin impaired SEMA7A-induced hCASMC proliferation and migration.Conclusions: SEMA7A triggers phenotype switching in VSMCs through the β-catenin signaling pathway and may serve as a potential therapeutic target for cardiovascular diseases.

Methotrexate and cardiovascular prevention: an appraisal of the current evidence.

New evidence continues to accumulate regarding a significant association between excessive inflammation and dysregulated immunity (local and systemic) and the risk of cardiovascular events in different patient cohorts. Whilst research has sought to identify novel atheroprotective therapies targeting inflammation and immunity, several marketed drugs for rheumatological conditions may serve a similar purpose. One such drug, methotrexate, has been used since 1948 for treating cancer and, more recently, for a wide range of dysimmune conditions. Over the last 30 years, epidemiological and experimental studies have shown that methotrexate is independently associated with a reduced risk of cardiovascular disease, particularly in rheumatological patients, and exerts several beneficial effects on vascular homeostasis and blood pressure control. This review article discusses the current challenges with managing cardiovascular risk and the new frontiers offered by drug discovery and drug repurposing targeting inflammation and immunity with a focus on methotrexate. Specifically, the article critically appraises the results of observational, cross-sectional and intervention studies investigating the effects of methotrexate on overall cardiovascular risk and individual risk factors. It also discusses the putative molecular mechanisms underpinning the atheroprotective effects of methotrexate and the practical advantages of using methotrexate in cardiovascular prevention, and highlights future research directions in this area.

In Vivo Profiling of the Vascular Cell Surface Proteome in Murine Models of Bacteremia.

Vascular dysfunction is a hallmark of systemic inflammatory responses such as bacterial sepsis. The luminal surface of the blood vessels is coated with a dense layer of glycans and proteoglycans, collectively known as the glycocalyx. Surface associated glycoproteins of endothelial origin, or derived from pericytes, intravascular leukocytes, and plasma, are other important components of the glycocalyx, constituting a vascular cell surface proteome that is dynamic, tissue-specific, and sensitive to changes in vascular homeostasis, blood infection, and inflammation. Here, we describe an experimental protocol to chemically tag and quantify the vascular cell surface proteome in murine models of bacteremia, in a time-resolved and organ-specific manner. This method facilitates the identification of markers of vascular activation and provides a molecular framework to understand the contribution of vascular dysfunction to the organ pathology of systemic inflammation.

The elusive brain perivascular fibroblast: a potential role in vascular stability and homeostasis.

In the brain, perivascular fibroblasts (PVFs) reside within the perivascular spaces (PVSs) of arterioles and large venules, however their physiological and pathophysiological roles remain largely unknown. PVFs express numerous extracellular matrix proteins that are found in the basement membrane and PVS surrounding large diameter vessels. PVFs are sandwiched between the mural cell layer and astrocytic endfeet, where they are poised to interact with mural cells, perivascular macrophages, and astrocytes. We draw connections between the more well-studied PVF pro-fibrotic response in ischemic injury and the less understood thickening of the vascular wall and enlargement of the PVS described in dementia and neurodegenerative diseases. We postulate that PVFs may be responsible for stability and homeostasis of the brain vasculature, and may also contribute to changes within the PVS during disease.

Second International Pulmonary Hypertension/Heart Failure Symposium—Structural heart disease, right ventricular dysfunction, and stem cell therapy: The European Pediatric Pulmonary Vascular Disease Network

Second International Pulmonary Hypertension/Heart Failure Symposium—Structural heart disease, right ventricular dysfunction, and stem cell therapy: The European Pediatric Pulmonary Vascular Disease Network