Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium

Yao, Yucheng; Jumabay, Medet; Ly, Albert; Radparvar, Melina; Wang, Anthony H.; Abdmaulen, Raushan; Boström, Kristina I.

doi:10.1182/blood-2011-10-385906

Cited by 56 publications

(64 citation statements)

References 35 publications

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“…BMP9 is expressed in the mouse aortic endothelium, 9 suggesting that it may function both as an endothelial cell-autonomous (ie, autocrine) as well as a circulating or local paracrine factor. Therefore, to gain insight into potential endothelial cell autocrine functions of BMP9, we modified a well-characterized SVEC 19 to For personal use only.…”

Section: Expression Of Bmp9 In Endothelial Cells Results In Secretionmentioning

confidence: 99%

“…6 The ALK1-endoglin signaling complex in endothelial cells is activated by BMP9, 7 a circulating cytokine produced in the liver reticuloendothelium 8 and endothelial cells, including those lining the mouse aorta. 9 BMP9 interacts with endoglin and ALK1 to activate signaling pathways 7 that promote endothelial cell quiescence 10 and vessel maturation. 11 Several endothelial cell-derived factors, including BMP9, are known to regulate vessel maturation via paracrine recruitment of other cell types.…”

Section: Introductionmentioning

confidence: 99%

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BMP9 regulates endoglin-dependent chemokine responses in endothelial cells

Young

Conley

Romero

et al. 2012

Blood

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BMP9 signaling has been implicated in hereditary hemorrhagic telangiectasia (HHT) and vascular remodeling, acting via the HHT target genes, endoglin and ALK1. This study sought to identify endothelial BMP9-regulated proteins that could affect the HHT phenotype. Gene ontology analysis of cDNA microarray data obtained after BMP9 treatment of primary human endothelial cells indicated regulation of chemokine, adhesion, and inflammation pathways. These responses included the up-regulation of the chemokine CXCL12/SDF1 and down-regulation of its receptor CXCR4. Quantitative mass spectrometry identified additional secreted proteins, including the chemokine CXCL10/IP10. RNA knockdown of endoglin and ALK1 impaired SDF1/CXCR4 regulation by BMP9. Because of the association of SDF1 with ischemia, we analyzed its expression under hypoxia in response to BMP9 in vitro, and during the response to hindlimb ischemia, in endoglin-deficient mice. BMP9 and hypoxia were additive inducers of SDF1 expression. Moreover, the data suggest that endoglin deficiency impaired SDF1 expression in endothelial cells in vivo. Our data implicate BMP9 in regulation of the SDF1/CXCR4 chemokine axis in endothelial cells and point to a role for BMP9 signaling via endoglin in a switch from an SDF1-responsive autocrine phenotype to an SDF1 nonresponsive paracrine state that represses endothelial cell migration and may promote vessel maturation. IntroductionEndoglin directly interacts with the TGF-␤ receptors, 1 including ALK1, 2 and modulates TGF-␤ and bone morphogenetic protein (BMP) signaling. 3 Mutations in either endoglin 4 or ALK1 5 increase the risk of hereditary hemorrhagic telangiectasia (HHT1 and HHT2, respectively), whose symptoms include arteriovenous malformation, tissue ischemia, and reperfusion defects. 6 The ALK1-endoglin signaling complex in endothelial cells is activated by BMP9, 7 a circulating cytokine produced in the liver reticuloendothelium 8 and endothelial cells, including those lining the mouse aorta. 9 BMP9 interacts with endoglin and ALK1 to activate signaling pathways 7 that promote endothelial cell quiescence 10 and vessel maturation. 11 Several endothelial cell-derived factors, including BMP9, are known to regulate vessel maturation via paracrine recruitment of other cell types. 12 Moreover, our recent work using nonendothelial cells implicates endoglin in the regulation of tumor neoangiogenesis via the secreted insulin-like growth factor binding protein 4. 13 Therefore, elucidation of the role of BMP9 signaling, specifically in terms of its effects on the expression of endothelial cell-secreted factors, is needed to better understand the mechanisms by which BMP9 affects vessel maturation, integrity, the vascular response to injury, and how deficiency in either endoglin or ALK1 impacts vessel integrity and cause HHT.Stromal-derived factor 1 (SDF1, CXCL12) is a chemokine that signals via the chemokine receptor, CXCR4, to modulate hypoxiainduced angiogenesis. 14 SDF1 regulates both endothelial cellmediated paracrine signaling ...

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Section: Expression Of Bmp9 In Endothelial Cells Results In Secretionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BMP9 regulates endoglin-dependent chemokine responses in endothelial cells

Young

Conley

Romero

et al. 2012

Blood

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“…Endochondral bone formation occurs in close spatial and temporal association and proximity to capillary invasion, so that angiogenesis and osteogenesis must be tightly coupled (Olsen et al, 2000;Wan et al, 2010;Wang et al, 2007). Conflicting results have implicated BMP9 as either an angiogenesis inducer in endothelial cells (Castonguay et al, 2011;Cunha et al, 2010;Mitchell et al, 2010;Park et al, 2012;Scharpfenecker et al, 2007;Suzuki et al, 2010;Yao et al, 2012) or as a potent anti-angiogenic factor (David et al, 2008). Although it is well recognized that osteogenic and angiogenic pathways are well coordinated during bone formation (Wan et al, 2010), it is unclear how these processes are linked in MSCs stimulated by osteogenic factors, such as BMPs.…”

Section: Introductionmentioning

confidence: 99%

BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells

Jiang

Huang

et al. 2013

Journal of Cell Science

110

112

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SummaryMesenchymal stromal progenitor cells (MSCs) are multipotent progenitors that can be isolated from numerous tissues. MSCs can undergo osteogenic differentiation under proper stimuli. We have recently demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most osteogenic BMPs. As one of the least studied BMPs, BMP9 has been shown to regulate angiogenesis in endothelial cells. However, it is unclear whether BMP9-regulated angiogenic signaling plays any important role in the BMP9-initiated osteogenic pathway in MSCs. Here, we investigate the functional role of hypoxia-inducible factor 1a (HIF1a)-mediated angiogenic signaling in BMP9-regulated osteogenic differentiation of MSCs. We find that BMP9 induces HIF1a expression in MSCs through Smad1/5/8 signaling. Exogenous expression of HIF1a potentiates BMP9-induced osteogenic differentiation of MSCs both in vitro and in vivo. siRNA-mediated silencing of HIF1a or HIF1a inhibitor CAY10585 profoundly blunts BMP9-induced osteogenic signaling in MSCs. HIF1a expression regulated by cobalt-induced hypoxia also recapitulates the synergistic effect between HIF1a and BMP9 in osteogenic differentiation. Mechanistically, HIF1a is shown to exert its synergistic effect with BMP9 by inducing both angiogenic signaling and osteogenic signaling in MSCs. Thus, our findings should not only expand our understanding of the molecular basis behind BMP9-regulated osteoblastic lineage-specific differentiation, but also provide an opportunity to harness the BMP9-induced synergy between osteogenic and angiogenic signaling pathways in regenerative medicine.

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“…Tissue sections were fixed, processed, and stained as previously described (35). Immunofluorescence was performed as previously described in detail (36,37).…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblotting was performed as previously described (35). Equal amounts of cellular protein were used.…”

Section: Methodsmentioning

confidence: 99%

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

Yao¹,

Yao²,

Radparvar³

et al. 2013

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

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Significance Cerebral arteriovenous malformations (AVMs) are common vascular abnormalities that may lead to strokes. Signaling by bone morphogenetic proteins (BMPs) and Notch play important roles in the formation of cerebral AVMs, but the cross-talk between the pathways is poorly understood. We report that gene deletion of matrix Gla protein (MGP), a BMP inhibitor, causes cerebral AVMs in mice by activating activin receptor-like kinase 1, a BMP receptor. This activation enhances Notch activity and disrupts endothelial cell differentiation by inducing the Notch ligands Jagged 1 and 2. Reducing Jagged 1 and 2 expression prevents the disruption in differentiation and AVM formation. The findings suggest that MGP maintains the balance between BMP and Notch signaling and promotes a normal brain vasculature.

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Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium

Cited by 56 publications

References 35 publications

BMP9 regulates endoglin-dependent chemokine responses in endothelial cells

BMP9 regulates endoglin-dependent chemokine responses in endothelial cells

BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

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