Anti-Inflammatory and Antiatherogenic Role of BMP Receptor II in Endothelial Cells

Kim, Chan Woo; Song, Hannah; Kumar, Sandeep; Nam, Douglas; Kwon, Hyuk Sang; Chang, Kuo‐Hsuan; Son, Dong Ju; Kang, Dong‐Won; Brodie, Seth A.; Weiss, Daiana; Vega, J. David; Alberts-Grill, Noah; Griendling, Kathy K.; Taylor, W. Robert; Jo, Hanjoong

doi:10.1161/atvbaha.112.300287

Cited by 85 publications

(92 citation statements)

References 54 publications

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“…In contrast to the proinflammatory role of BMPs, a recent study by Kim et al (17) demonstrated that BMPRII plays a constitutively antiinflammatory and antiatherogenic role in ECs. Loss of BMPRII expression causes endothelial inflammation and atherosclerosis (17). In the present study, we did not attempt to define the in vivo role of BMPRII in endothelial and vascular functions.…”

Section: Discussionmentioning

confidence: 91%

Different modes of endothelial–smooth muscle cell interaction elicit differential β-catenin phosphorylations and endothelial functions

Chang¹,

Chen

Lee

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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β-Catenin phosphorylation plays important roles in modulating its functions, but the effects of different phosphorylated forms of β-catenin in response to heterocellular interaction are unclear. Here we investigated whether distinct modes of phosphorylation on β-catenin could be triggered through heterocellular interactions between endothelial cells (ECs) and smooth muscle cells (SMCs), and the consequent modulation of EC functions. ECs were cocultured with SMCs to initiate direct contact and paracrine interaction. EC-SMC coculture induced EC β-catenin phosphorylations simultaneously at tyrosine 142 (Tyr142) and serine 45/threonine 41 (Ser45/Thr41) at the cytoplasm/nuclei and the membrane, respectively. Treating ECs with SMC-conditional medium induced β-catenin phosphorylation only at Ser45/Thr41. These findings indicate that different phosphorylation effects of EC-SMC coculture were induced through heterocellular direct contact and paracrine effects, respectively. Using specific blocking peptides, antagonists, and siRNAs, we found that the β-catenin Tyr142-phosphorylation was mediated by connexin 43/Fer and that the β-catenin Ser45/ Thr41-phosphorylation was mediated by SMC-released bone morphogenetic proteins through VE-cadherin and bone morphogenetic protein receptor-II/Smad5. Transfecting ECs with β-cateninTyr142 or -Ser45 mutants showed that these two phosphorylated forms of β-catenin modulate differential EC function: The Tyr142-phosphorylated β-catenin stimulates vascular cell-adhesion molecule-1 expression to increase EC-monocytic adhesion, but the Ser45/Thr41-phosphorylated β-catenin attenuates VE-cadherindependent junction structures to increase EC permeability. Our findings provide new insights into the understanding of regulatory complexities of distinct modes of β-catenin phosphorylations under EC-SMC interactions and suggest that different phosphorylated forms of β-catenin play important roles in modulating vascular pathophysiology through different heterocellular interactions.endothelial permeability | inflammation I t is known that β-catenin is a major component of cell junctions and a gene transcription factor that plays important roles in regulating cell functions (1). A well-known regulatory mechanism of β-catenin is through the N-terminal serial phosphorylations at serine 45 (Ser45) and then threonine 41 (Thr41)/ Ser33/37, which consequently initiate the self-degradation of β-catenin. However, recent evidence indicates that the effects of different phosphorylated modes of β-catenin, including tyrosine (Tyr) 142/654 and Ser-45, on its activity regulations are more complex than originally understood (1, 2). For example, β-catenin Ser45-phosphorylation does not necessarily lead to its degradation, but instead modulates cell migration in tumor cells (2); β-catenin Tyr142/654-phosphorylation by membrane receptor tyrosine kinases (RTKs) or cytosolic Fyn/Fer tyrosine kinases increases its transcription cofactor activity to regulate target gene activations in epithelial and tumor cells (1, 3). In add...

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Section: Discussionmentioning

confidence: 91%

Different modes of endothelial–smooth muscle cell interaction elicit differential β-catenin phosphorylations and endothelial functions

Chang¹,

Chen

Lee

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, differential methylation seems to explain the cell-specific expression of the superoxide dismutase, and the endothelial nitric oxide synthase genes (26,27). Other studies, however, have shown similarities in PAEC and systemic EC dysfunction studied in relation to loss of BMPR2 (19,28), and to PAH in general (29). Here, we provide evidence for the first time that IPAH/HPAH PAEC and iPSC-EC from the same individuals have similar functional impairment related at least in part to reduced BMPR2 and downstream signaling, and gene expression of COL4A2.…”

Section: Discussionmentioning

confidence: 99%

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

Chappell³

et al. 2017

Am J Respir Crit Care Med

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Rationale: Idiopathic or heritable pulmonary arterial hypertension is characterized by loss and obliteration of lung vasculature. Endothelial cell dysfunction is pivotal to the pathophysiology, but different causal mechanisms may reflect a need for patient-tailored therapies.Objectives: Endothelial cells differentiated from induced pluripotent stem cells were compared with pulmonary arterial endothelial cells from the same patients with idiopathic or heritable pulmonary arterial hypertension, to determine whether they shared functional abnormalities and altered gene expression patterns that differed from those in unused donor cells. We then investigated whether endothelial cells differentiated from pluripotent cells could serve as surrogates to test emerging therapies.Methods: Functional changes assessed included adhesion, migration, tube formation, and propensity to apoptosis. Expression of bone morphogenetic protein receptor type 2 (BMPR2) and its target, collagen IV, signaling of the phosphorylated form of the mothers against decapentaplegic proteins (pSMAD1/5), and transcriptomic profiles were also analyzed.Measurements and Main Results: Native pulmonary arterial and induced pluripotent stem cell-derived endothelial cells from patients with idiopathic and heritable pulmonary arterial hypertension compared with control subjects showed a similar reduction in adhesion, migration, survival, and tube formation, and decreased BMPR2 and downstream signaling and collagen IV expression. Transcriptomic profiling revealed high kisspeptin 1 (KISS1) related to reduced migration and low carboxylesterase 1 (CES1), to impaired survival in patient cells. A beneficial angiogenic response to potential therapies, FK506 and Elafin, was related to reduced slit guidance ligand 3 (SLIT3), an antimigratory factor.Conclusions: Despite the site of disease in the lung, our study indicates that induced pluripotent stem cell-derived endothelial cells are useful surrogates to uncover novel features related to disease mechanisms and to better match patients to therapies.

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“…This resistance is linked to increased production of IL-6 and IL-8, as the normal growthinhibitory effect of transforming growth factor-b is restored by coincubation with neutralizing antibodies to either IL-6 or IL-8 (35). In addition, siRNA-mediated knockdown of BMPR-II increased monocyte adhesion and induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels in human umbilical vein endothelial cells (36). Burton and colleagues (37) showed enhanced leukocyte transmigration through BMPR-II-deficient endothelial cells compared with mock-transfected controls.…”

Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein Receptor Type II Deficiency and Increased Inflammatory Cytokine Production. A Gateway to Pulmonary Arterial Hypertension

Soon

Crosby

Southwood

et al. 2015

Am J Respir Crit Care Med

127

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Rationale: Mutations in bone morphogenetic protein receptor type II (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (PAH). However, disease penetrance is only 20-30%, suggesting a requirement for additional triggers. Inflammation is emerging as a key disease-related factor in PAH, but to date there is no clear mechanism linking BMPR-II deficiency and inflammation.Objectives: To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH.Methods: We used pulmonary artery smooth muscle cells from Bmpr2 1/2 mice and patients with BMPR2 mutations and compared them with wild-type controls. For the in vivo model, we used mice heterozygous for a null allele in Bmpr2 (Bmpr2 1/2) and wild-type littermates.Measurements and Main Results: Acute exposure to LPS increased lung and circulating IL-6 and KC (IL-8 analog) levels in Bmpr21/2 mice to a greater extent than in wild-type controls. Similarly, pulmonary artery smooth muscle cells from Bmpr2 1/2 mice and patients with BMPR2 mutations produced higher levels of IL-6 and KC/IL-8 after lipopolysaccharide stimulation compared with controls. BMPR-II deficiency in mouse and human pulmonary artery smooth muscle cells was associated with increased phospho-STAT3 and loss of extracellular superoxide dismutase. Chronic lipopolysaccharide administration caused pulmonary hypertension in Bmpr2 1/2 mice but not in wild-type littermates. Coadministration of tempol, a superoxide dismutase mimetic, ameliorated the exaggerated inflammatory response and prevented development of PAH.Conclusions: This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.

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Anti-Inflammatory and Antiatherogenic Role of BMP Receptor II in Endothelial Cells

Cited by 85 publications

References 54 publications

Different modes of endothelial–smooth muscle cell interaction elicit differential β-catenin phosphorylations and endothelial functions

Different modes of endothelial–smooth muscle cell interaction elicit differential β-catenin phosphorylations and endothelial functions

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

Bone Morphogenetic Protein Receptor Type II Deficiency and Increased Inflammatory Cytokine Production. A Gateway to Pulmonary Arterial Hypertension

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