ABSTRACT
Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.
Subject(s)
Hypertension, Pulmonary , Vascular Remodeling , Mice , Humans , Animals , Pericytes/metabolism , Endothelial Cells/metabolism , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/metabolism , Hypoxia/genetics , Hypoxia/metabolism , LungABSTRACT
OBJECTIVE: To assess the extent and resolution of pulmonary hypertension (PH), cardiovascular factors, and echocardiographic findings associated with mortality in infants and children with vein of Galen malformation (VOGM). STUDY DESIGN: We performed a retrospective review of 49 consecutive children with VOGM admitted to Boston Children's Hospital from 2007 to 2020. Patient characteristics, echocardiographic data, and hospital course were analyzed for 2 cohorts based on age at presentation to Boston Children's Hospital: group 1 (age ≤60 days) or group 2 (age >60 days). RESULTS: Overall hospital survival was 35 of 49 (71.4%); 13 of 26 (50%) in group 1 and 22 of 23 (96%) in group 2 (P < .001). High-output PH (P = .01), cardiomegaly (P = .011), intubation (P = .019), and dopamine use (P = .01) were significantly more common in group 1 than group 2. Among patients in group 1, congestive heart failure (P = .015), intubation (P < .001), use of inhaled nitric oxide (P = .015) or prostaglandin E1 (P = .030), suprasystemic PH (P = .003), and right-sided dilation were significantly associated with mortality; in contrast, left ventricular volume and function, structural congenital heart disease, and supraventricular tachycardia were not associated. Inhaled nitric oxide achieved no clinical benefit in 9 of 11 treated patients. Resolution of PH was associated with overall survival (P < .001). CONCLUSIONS: VOGM remains associated with substantial mortality among infants presenting at ≤60 days of life owing to factors associated with high output PH. Resolution of PH is an indicator associated with survival and a surrogate end point for benchmarking outcomes.
Subject(s)
Hypertension, Pulmonary , Vein of Galen Malformations , Humans , Infant , Child , Infant, Newborn , Hypertension, Pulmonary/complications , Vein of Galen Malformations/complications , Vein of Galen Malformations/diagnostic imaging , Vein of Galen Malformations/therapy , Nitric Oxide , VeinsABSTRACT
INTRODUCTION: Cell-free plasma hemoglobin is associated with poor outcome in patients with sepsis. Extracellular hemoglobin and secondarily released heme amplify inflammation in the presence of microbial TLR ligands and/or endogenous mediators. Hemopexin, a plasma protein that binds heme with extraordinary affinity, blocks these effects and has been proposed as a possible treatment approach to decrease inflammation in critically ill patients. METHODS: We studied mouse models of endotoxemia, burn wound infections and peritonitis in order to assess if a repletion strategy for hemopexin might be reasonable. We also measured hemopexin in small numbers of three patient populations that might be logical groups for hemopexin therapy: patients with sepsis and ARDS, patients with severe burns, and premature infants. RESULTS: Despite severe disease, mean plasma hemopexin levels were increased above baseline in each murine model. However, plasma hemopexin levels were decreased or markedly decreased in many patients in each of the three patient populations. CONCLUSIONS: Potentially different behavior of hemopexin in mice and humans may be important to consider when utilizing murine models to represent acute human inflammatory diseases in which heme plays a role. The findings raise the possibility that decreased hemopexin could result in insufficiently neutralized or cleared heme in some patients with ARDS, burns, or in premature infants who might be candidates to benefit from hemopexin administration.
Subject(s)
Burns/blood , Disease Models, Animal , Hemopexin/metabolism , Infant, Premature/blood , Sepsis/blood , Severity of Illness Index , Adolescent , Adult , Animals , Biomarkers/blood , Burns/diagnosis , Female , Humans , Infant, Newborn , Inflammation/blood , Inflammation/diagnosis , Male , Mice , Mice, Inbred C57BL , Sepsis/diagnosis , Young AdultABSTRACT
Pulmonary hypertension (PH) is a life-threatening disease with unclear vascular mechanisms. We tested whether PH involves abnormal pulmonary vasoconstriction and impaired vasodilation. Male Sprague-Dawley rats were exposed to hypoxia (9% O(2)) for 2 weeks or injected with single dose of monocrotaline (MCT, 60 mg/kg s.c.). Control rats were normoxic or injected with saline. After the hemodynamic measurements were performed, pulmonary and mesenteric arteries were isolated for measurement of vascular function. Hematocrit was elevated in hypoxic rats. Right ventricular systolic pressure and Fulton's Index [right/(left + septum) ventricular weight] were greater in hypoxic and MCT-treated rats than in normoxic rats. Pulmonary artery contraction by phenylephrine and 96 mM KCl was less in hypoxic and MCT-treated rats than in normoxic rats. Acetylcholine-induced relaxation was less in the pulmonary arteries of hypoxic and MCT-treated rats than of normoxic rats, suggesting reduced effects of endothelium-derived vasodilators. The nitric oxide synthase inhibitor, N(omega)-nitro-l-arginine methyl ester, and the guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, inhibited acetylcholine relaxation, suggesting that it was mediated by nitric oxide (NO)-cGMP. The NO donor sodium nitroprusside caused less relaxation in the pulmonary arteries of hypoxic and MCT-treated than of normoxic rats, suggesting decreased responsiveness of vascular smooth muscle cells (VSMCs) to vasodilators. Phenylephrine and KCl contraction and acetylcholine and sodium nitroprusside relaxation were not different in the mesenteric arteries from all groups. In lung tissue sections, the wall thickness of pulmonary arterioles was greater in hypoxic and MCT-treated rats than in normoxic rats. The specific reductions in pulmonary, but not systemic, arterial vasoconstriction and vasodilation in hypoxia- and MCT-induced PH are consistent with the possibility of de-differentiation of pulmonary VSMCs to a more proliferative/synthetic and less contractile phenotype in PH.
Subject(s)
Hypertension, Pulmonary/physiopathology , Nitric Oxide/physiology , Pulmonary Artery/physiopathology , Vasoconstriction/physiology , Vasodilation/physiology , Animals , Disease Models, Animal , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/pathology , Hypoxia/physiopathology , Lung/pathology , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/physiopathology , Monocrotaline , Myocardium/pathology , Pulmonary Artery/drug effects , Rats , Rats, Sprague-Dawley , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacologyABSTRACT
Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and ß-thalassemia1. BCL11A represses the genes encoding HbF and regulates human hemoglobin switching through variation in its expression during development2-7. However, the mechanisms underlying the developmental expression of BCL11A remain mysterious. Here we show that BCL11A is regulated at the level of messenger RNA (mRNA) translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a pattern reciprocal to that of BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, we show that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independently of its role in regulating let-7 microRNAs, and that BCL11A is the major target of LIN28B-mediated HbF induction. Our results reveal a previously unappreciated mechanism underlying human hemoglobin switching that illuminates new therapeutic opportunities.
Subject(s)
Hemoglobins/metabolism , RNA-Binding Proteins/metabolism , Repressor Proteins/genetics , Adult , Animals , Binding Sites , Cells, Cultured , Erythroid Cells/metabolism , Erythropoiesis/genetics , Gene Expression Regulation , Hemoglobins/genetics , Humans , Infant, Newborn , MicroRNAs/metabolism , Protein Biosynthesis , RNA, Messenger/metabolism , RNA, Ribosomal, 18S/metabolism , RNA-Binding Proteins/genetics , Repressor Proteins/metabolism , Ribosomes/genetics , Ribosomes/metabolismABSTRACT
Intrauterine closure of the fetal ductus arteriosus is a rare but serious condition. It can lead to congestive heart failure, fetal hydrops, and fetal death. No intrauterine intervention is currently available to treat this condition. Postnatally, it can present as pulmonary hypertension and can be associated with high mortality and morbidity. Postnatal therapies aimed at pulmonary hypertension or with medications that maintain the patency of the ductus arteriosus are variably successful. We present the neonatal course of a full-term neonate with severe pulmonary hypertension and intrauterine closure of the ductus arteriosus who survived to early infancy.