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Germline mutations involving small mothers against decapentaplegic-transforming growth factor-β (SMAD-TGF-β) signaling are an important but rare cause of pulmonary arterial hypertension (PAH), which is a disease characterized, in part, by vascular fibrosis and hyperaldosteronism (ALDO). We developed and analyzed a fibrosis protein-protein network (fibrosome) in silico, which predicted that the SMAD3 target neural precursor cell expressed developmentally down-regulated 9 (NEDD9) is a critical ALDO-regulated node underpinning pathogenic vascular fibrosis. Bioinformatics and microscale thermophoresis demonstrated that oxidation of Cys18 in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interactions in vitro. This effect was reproduced by ALDO-induced oxidant stress in cultured human pulmonary artery endothelial cells (HPAECs), resulting in impaired NEDD9 proteolytic degradation, increased NEDD9 complex formation with Nk2 homeobox 5 (NKX2-5), and increased NKX2-5 binding to COL3A1 Up-regulation of NEDD9-dependent collagen III expression corresponded to changes in cell stiffness measured by atomic force microscopy. HPAEC-derived exosomal signaling targeted NEDD9 to increase collagen I/III expression in human pulmonary artery smooth muscle cells, identifying a second endothelial mechanism regulating vascular fibrosis. ALDO-NEDD9 signaling was not affected by treatment with a TGF-β ligand trap and, thus, was not contingent on TGF-β signaling. Colocalization of NEDD9 with collagen III in HPAECs was observed in fibrotic pulmonary arterioles from PAH patients. Furthermore, NEDD9 ablation or inhibition prevented fibrotic vascular remodeling and pulmonary hypertension in animal models of PAH in vivo. These data identify a critical TGF-β-independent posttranslational modification that impairs SMAD3-NEDD9 binding in HPAECs to modulate vascular fibrosis and promote PAH.

Bone morphogenetic proteins (BMPs) and their receptors, known to be essential regulators of embryonic patterning and organogenesis, are also critical for the regulation of cardiovascular structure and function. In addition to their contributions to syndromic disorders including heart and vascular development, BMP signalling is increasingly recognized for its influence on endocrine-like functions in postnatal cardiovascular and metabolic homeostasis. In this Review, we discuss several critical and novel aspects of BMP signalling in cardiovascular health and disease, which highlight the cell-specific and context-specific nature of BMP signalling. Based on advancing knowledge of the physiological roles and regulation of BMP signalling, we indicate opportunities for therapeutic intervention in a range of cardiovascular conditions including atherosclerosis and pulmonary arterial hypertension, as well as for anaemia of inflammation. Depending on the context and the repertoire of ligands and receptors involved in specific disease processes, the selective inhibition or enhancement of signalling via particular BMP ligands (such as in atherosclerosis and pulmonary arterial hypertension, respectively) might be beneficial. The development of selective small molecule antagonists of BMP receptors, and the identification of ligands selective for BMP receptor complexes expressed in the vasculature provide the most immediate opportunities for new therapies.

Dysregulation of microRNA-21 (miR-21) is independently associated with HIV infection, pulmonary arterial hypertension (PAH), and hepatitis C virus (HCV) infection. To assess the expression of miR-21 in these overlapping comorbidities, we measured plasma miR-21 in HIV with and without PAH and then stratified by concomitant HCV infection. MiR-21 was increased in HIV and HIV-PAH versus uninfected subjects, but it did not differ between these groups. HIV/HCV coinfection correlated with even higher miR-21 levels within the HIV-infected population. These data reveal specific regulation of plasma miR-21 in HIV, HIV/HCV coinfection, and PAH and suggest that miR-21 may integrate complex disease-specific signaling in the setting of HIV infection.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by activin A, an effect countered by inhibition of anti-activin A via monoclonal antibody treatment. Hence, we surmised that anti-ACVR1 antibodies that block activation of ACVR1 by ligands should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated anti-ACVR1 monoclonal antibodies that block ACVR1's activation by its ligands. Surprisingly, in vivo, these anti-ACVR1 antibodies stimulated HO and activated signaling of FOP-mutant ACVR1. This property was restricted to FOPmutant ACVR1 and resulted from anti-ACVR1 antibody-mediated dimerization of ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These results uncover an additional property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as therapeutics for FOP., Introduction Fibrodysplasia ossificans progressiva (FOP) (OMIM #135100) is a rare, autosomal dominant disorder characterized by congenital skeletal dysplasias and progressive and cumulative heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, [...]

The authors discuss a study which evaluated the concept that deficiency of BMP9, a circulating ligand of TGFΒ superfamily produced by the liver, contributes to the development of hepatopulmonary syndrome ( HPS). Topics include BMP9 concentrations in patients with HPS or combined HPS and portopulmonary hypertension (PoPH) and factors that may have influenced the increased capacity of BMP9 to discriminate HPS versus PoPH compared with previous cohorts.

Maternal cigarette smoking during pregnancy remains one of the most common and preventable causes of fetal growth restriction (FGR), a condition in which a fetus is unable to achieve its genetically determined potential size. Even though epidemiologic evidence clearly links maternal cigarette smoking with FGR, insight into the molecular mechanisms of cigarette smoke-induced FGR is lacking. Here, we performed transcriptional profiling of placentas obtained from smoking mothers who delivered growth-restricted infants and identified secreted frizzled-related protein 1 (sFRPI), an extracellular antagonist of endogenous WNT signaling, as a candidate molecule. sFRPI mRNA and protein levels were markedly upregulated (-10fold) in placentas from smoking mothers compared with those from nonsmokers. In pregnant mice, adenovirus-mediated overexpression of sFRP1 led to FGR, increased karyorrhexis in the junctional zone, and decreased proliferation of labyrinthine trophoblasts. Consistent with our hypothesis that placental WNT signaling is suppressed in maternal smokers, we found that exposure to carbon monoxide analogs led to reduced WNT signaling, increased SFRP1 mRNA expression, and decreased cellular proliferation in a trophoblast cell line. Moreover, administration of carbon monoxide analogs to pregnant mice in late gestation led to FGR. In summary, our results indicate that the increased placental expression of sFRP1 seen in smokers impairs fetal growth by inhibiting WNT signaling and trophoblast proliferation., Introduction Fetal growth restriction (FGR), a condition in which a fetus is unable to achieve its genetically determined potential size, results in substantial perinatal and neonatal morbidity and mortality (1). [...]

Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH., Heritable and idiopathic PAH are characterized by narrowing and obliteration of precapillary pulmonary arteries secondary to proliferation and apoptosis resistance of endothelial cells, smooth muscle cells and fibroblasts (1). The [...]