Bone Morphogenetic Protein Binding Endothelial Regulator (BMPER) Regulates Vascular Inflammatory Responses in Endothelial Cells (original) (raw)
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Arteriosclerosis, Thrombosis, and Vascular Biology, 2012
Objective-Bone morphogenetic proteins (Bmps) are important mediators of inflammation and atherosclerosis, though their mechanism of action is not fully understood. To better understand the contribution of the Bmp signaling pathway in vascular inflammation, we investigated the role of Bmper (Bmp endothelial cell precursor-derived regulator), an extracellular Bmp modulator, in an induced in vivo model of inflammation and atherosclerosis. Methods and Results-We crossed apolipoprotein E-deficient (ApoE −/− ) mice with mice missing 1 allele of Bmper (Bmper +/− mice used in the place of Bmper −/− mice that die at birth) and measured the development of atherosclerosis in mice fed a high-fat diet. Bmper haploinsufficiency in ApoE −/− mice (Bmper +/− ;ApoE −/− mice) led to a more severe phenotype compared with Bmper +/+ ;ApoE −/− mice. Bmper +/− ;ApoE −/− mice also exhibited increased Bmp activity in the endothelial cells in both the greater and lesser curvatures of the aortic arch, suggesting a role for Bmper in regulating Bmp-mediated inflammation associated with laminar and oscillatory shear stress. Small interfering RNA knockdown of Bmper in human umbilical vein endothelial cells caused a dramatic increase in the inflammatory markers intracellular adhesion molecule 1 and vascular cell adhesion molecule 1 at rest and after exposure to oscillatory and laminar shear stress. Conclusion-We conclude that Bmper is a critical regulator of Bmp-mediated vascular inflammation and that the finetuning of Bmp and Bmper levels is essential in the maintenance of normal vascular homeostasis. (Arterioscler Thromb Vasc Biol. 2012;32:2214-2222.)
LRP1-Dependent BMPER Signaling Regulates Lipopolysaccharide-Induced Vascular Inflammation
Arteriosclerosis, thrombosis, and vascular biology, 2017
Bacterial endotoxin (lipopolysaccharide)-mediated sepsis involves dysregulated systemic inflammation, which injures the lung and other organs, often fatally. Vascular endothelial cells act as both targets and mediators of lipopolysaccharide-induced inflammatory responses. Dysfunction of endothelium results in increases of proinflammatory cytokine production and permeability leakage. BMPER (bone morphogenetic protein-binding endothelial regulator), an extracellular modulator of bone morphogenetic protein signaling, has been identified as a vital component in chronic endothelial inflammatory responses and atherosclerosis. However, it is unclear whether BMPER also regulates inflammatory response in an acute setting such as sepsis. To address this question, we investigated the role of BMPER during lipopolysaccharide-induced acute lung injury. Mice missing 1 allele of BMPER (BMPER(+/-) mice used in the place of BMPER(-/-) mice that die at birth) were used for lipopolysaccharide challenge...
American Journal of Physiology-heart and Circulatory Physiology, 2008
Csiszar A, Labinskyy N, Jo H, Ballabh P, Ungvari Z. Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells. There is increasing evidence that TGF- family member cytokine bone morphogenetic protein (BMP)-4 plays different pathophysiological roles in the pulmonary and systemic circulation. Upregulation of BMP-4 has been linked to atherosclerosis and hypertension in the systemic circulation, whereas disruption of BMP-4 signaling is associated with the development of pulmonary hypertension. To test the hypothesis that BMP-4 elicits differential effects in the pulmonary and systemic circulation, we compared the prooxidant and proinflammatory effects of BMP-4 in cultured human coronary arterial endothelial cells (CAECs) and pulmonary arterial endothelial cells (PAECs). We found that BMP-4 (from 0.3 to 10 ng/ml) in CAECs increased O2 •Ϫ and H2O2 generation, induced NF-B activation, upregulated ICAM-1, and induced monocyte adhesiveness to ECs. In contrast, BMP-4 failed to induce oxidative stress or endothelial activation in PAECs. Also, BMP-4 treatment impaired acetylcholine-induced relaxation and increased O2 •Ϫ production in cultured rat carotid arteries, whereas cultured rat pulmonary arteries were protected from these adverse effects of BMP-4. Thus, we propose that BMP-4 exerts prooxidant, prohypertensive, and proinflammatory effects only in the systemic circulation, whereas pulmonary arteries are protected from these adverse effects of BMP-4. The vascular bed-specific endothelial effects of BMP-4 are likely to contribute to its differential pathophysiological role in the systemic and pulmonary circulation.
Pulmonary Circulation, 2019
The bone morphogenetic protein receptor II (BMPRII) signaling pathway is impaired in pulmonary arterial hypertension and mutations in the BMPR2 gene have been observed in both heritable and idiopathic pulmonary arterial hypertension. However, all BMPR2 mutation carriers do not develop pulmonary arterial hypertension, and inflammation could trigger the development of the disease in BMPR2 mutation carriers. Circulating levels and/or lung tissue expression of cytokines such as tumor necrosis factor-α or interleukin-18 are elevated in patients with pulmonary arterial hypertension and could be involved in the pathogenesis of pulmonary arterial hypertension. We consequently hypothesized that cytokines could trigger endothelial dysfunction in addition to impaired BMPRII signaling. Our aim was to determine whether impairment of BMPRII signaling might affect endothelium barrier function and adhesiveness to monocytes, in response to cytokines. BMPR2 was silenced in human lung microvascular en...
Journal of Biological Chemistry, 2011
Activation of bone morphogenetic protein (BMP) receptor II (BMPRII) promotes pulmonary artery endothelial cell (PAEC) survival, proliferation, and migration. Mutations to BMPRII are associated with the development of pulmonary arterial hypertension (PAH). Endothelial dysfunction, including decreased endothelial nitric-oxide synthase (eNOS) activity and loss of bioactive nitric oxide (NO), plays a prominent role in the development of PAH. We hypothesized that stimulation of BMPRII promotes normal PAEC function by activating eNOS. We report that BMPRII ligands, BMP2 and BMP4, (i) stimulate eNOS phosphorylation at a critical regulatory site, (ii) increase eNOS activity, and (iii) result in canonical changes in eNOS proteinprotein interactions. The stimulation of eNOS activity by BMPRII ligands was largely dependent on protein kinase A (PKA) activation, as demonstrated using the PKA inhibitors H89 and myristoylated PKI(6-22) amide. PAEC migration stimulated by BMP2 and BMP4 was inhibited by the NOS inhibitor L-nitroarginine methyl ester, providing functional evidence of eNOS activation. Furthermore, BMP2 and BMP4 failed to stimulate eNOS phosphorylation when BMPRII was knocked down by siRNA. Most important to the pathophysiology of the disease, BMP2 and BMP4 failed to stimulate eNOS phosphorylation in PAECs isolated from patients with mutations in the BMPR2 gene. These data demonstrate a new action of BMPs/ BMPRII in the pulmonary endothelium and provide novel mechanistic insight into the pathogenesis of PAH.
Circulation Research, 2008
Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. BMPER (BMP endothelial cell precursor-derived regulator) is a differentially expressed protein in embryonic endothelial precursor cells. In earlier work, we found that BMPER interacts with BMPs and when overexpressed antagonizes their function in embryonic axis formation. In contrast, in a BMPER-deficient zebrafish model, BMPER behaves as a BMP agonist. Furthermore, lack of BMPER induces a vascular phenotype in zebrafish that is driven by disarray of the intersomitic vasculature. Here, we investigate the impact of BMPER on endothelial cell function and signaling and elucidate its role in BMP-4 function in gain-and loss-of-function models. As shown by Western blotting and immunocytochemistry, BMPER is an extracellular matrix protein expressed by endothelial cells in skin, heart, and lung. We show that BMPER is a downstream target of FoxO3a and consistently exerts activating effects on endothelial cell sprouting and migration in vitro and in vivo. Accordingly, when BMPER is depleted from endothelial cells, sprouting is impaired. In terms of BMPER related intracellular signaling, we show that BMPER is permissive and necessary for Smad 1/5 phosphorylation and induces Erk1/2 activation. Most interestingly, BMPER is necessary for BMP-4 to exert its activating role in endothelial function and to induce Smad 1/5 activation. Vice versa, BMP-4 is necessary for BMPER activity. Taken together, BMPER is a dose-dependent endothelial cell activator that plays a unique and pivotal role in fine-tuning BMP activity in angiogenesis. (Circ Res. 2008;103:804-812.)
Bone Morphogenetic Protein2 Induces Proinflammatory Endothelial Phenotype
American Journal of Pathology, 2006
The transforming growth factor- superfamily member bone morphogenetic protein-2 (BMP-2) is up-regulated in atherosclerotic arteries; however, its effects on the endothelium are not well characterized. Using microdissected coronary arterial endothelial cells (CAECs) and cultured primary CAECs, we demonstrated endothelial mRNA expression of BMP-2 and BMP-4. The proinflammatory cytokine tumor necrosis factor-␣ and H 2 O 2 significantly increased endothelial expression of BMP-2 but not BMP-4. In organ culture, BMP-2 substantially decreased relaxation of rat carotid arteries to acetylcholine and increased production of reactive oxygen species, events inhibited by pharmacologically blocking protein kinase C (PKC) or NAD(P)H oxidase. BMP-2 activated nuclear factor-〉 in CAECs, and BMP-2 and BMP-4 substantially increased adhesion of monocytic THP-1 cells, which was reduced by pharmacologically inhibiting p42/44 MAP kinase pathway (also by siRNA downregulating ERK-1/2) or PKC. Incubation of rat carotid arteries with BMP-2 ex vivo also increased adhesion of mononuclear cells to the endothelium, requiring p42/44 MAP kinase and PKC. Western blotting showed that in CAECs and carotid arteries BMP-2 elicited phosphorylation of p42/44 MAP kinase, which was reduced by blocking MAP kinase kinase and PKC. Collectively, expression of BMP-2 is regulated by proinflammatory stimuli, and increased levels of BMP-2 induce endothelial dysfunction, oxidative stress, and endothelial activation. Thus, the proinflammatory effects of BMP-2 may play a role in vascular pathophysiology.
Journal of Biological Chemistry, 2012
Background: Bone Morphogenetic Proteins (BMP) pathway defects and inflammation are hallmarks of pulmonary arterial hypertension (PAH). Results: BMP signaling inhibits TNF␣-induced activation of NF-B by promoting an MRTF-A/NF-B inhibitory complex in pulmonary smooth muscle cells. Conclusion: BMPs binding to BMPR2 receptor play anti-inflammatory roles by inhibiting TNF␣ signaling via MRTF-A. Significance: Defining how BMP pathway dysfunction promotes vascular pro-inflammatory state is critical to PAH therapy. . 2 The abbreviations used are: PAH, pulmonary arterial hypertension; BMP, bone morphogenetic protein; MRTF, myocardin-related transcription factor; PASMC, pulmonary artery smooth muscle cells; SMC, smooth muscle cells; ICC, inflammatory cytokine and chemokine.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2012
Objective-The expression of bone morphogenetic proteins (BMPs) is enhanced in human atherosclerotic and calcific vascular lesions. While genetic gain-and loss-of-function experiments in mice have supported a causal role of BMP signaling in atherosclerosis and vascular calcification, it remains uncertain whether BMP signaling might be targeted pharmacologically to ameliorate both of these processes.
Bone Morphogenetic Protein-9 Controls Pulmonary Vascular Growth and Remodeling
BackgroundPulmonary arterial hypertension (PAH), a life-limiting condition characterized by dysfunction of pulmonary microvascular endothelium, is predisposed by mutations in several genes that are critical for the proper activation of specific bone morphogenetic protein (BMP) receptor complexes that phosphorylate intracellular Smad1/5/8 in endothelial cells. However, the functional importance of BMP-9 (GDF2), one of the high affinity ligands for ALK1 (ACVRL1) and BMPR-II (BMPR2), for the pulmonary microvasculature remains imperfectly understood.ObjectiveThe aim of this study was first to determine thein vivoimpact of BMP-9 deficiency on pulmonary vascular growth and remodeling, then to assess whether ALK1 expression can alter BMP-9 transcriptional signatures in human pulmonary microvascular endothelial cells (PMECs).MethodsCRISPR-Cas9gene editing was used to createGdf2knockout rats inSprague Dawleybackground. Computed micro-tomography (Micro-Ct) scan after Microfil perfusion was pe...