SM22α-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis

El-Bizri, Nesrine; Guignabert, Christophe; Wang, Lingli; Cheng, Alvan; Stankunas, Kryn; Chang, Ching Pin; Mishina, Yuji; Rabinovitch, Marlene

doi:10.1242/dev.017863

Cited by 60 publications

(51 citation statements)

References 59 publications

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“…Altogether, these results confirm that Msx genes act upstream of Bmp4 and Bmp7 in VSMC progenitors and that, as previously demonstrated (El Bizri et al, 2008), BMP signaling is required for Mmp2 expression. In culture, Mmp9 expression decreases dramatically and so no conclusion could be drawn for this gene.…”

Section: Research Articlesupporting

confidence: 90%

“…Manipulations that reduce BMP levels usually result in impairment of VSMC coverage and in a correlative dilation of the vessel, e.g. Flk1-driven deletion of Bmpr1a (Park et al, 2006), Sm22-driven deletion of Bmpr1a (El-Bizri et al, 2008), knockdown of Bmpr2 (Liu et al, 2007) and mutation of Smad5 (Yang et al, 1999). These phenotypes are strikingly similar to those we describe in the head vessels of the Sm22Cre Msx1/2 mutant.…”

Section: Proper Bmp Signaling In Head Vsmcs Depends On Msx Genesmentioning

confidence: 99%

“…Sm22-Cre-driven inactivation of Bmpr1a severely affects Mmp2 and Mmp9 expression in VSMCs, which leads to a reduction in mural cell coverage and consequent vessel dilation (El-Bizri et al, 2008). In head VSMCs, Msx genes seem to act upstream of BMP expression and consequently before BMP receptor activation, as the level of Smad phosphorylation is reduced in the double mutant.…”

Section: Research Articlementioning

confidence: 99%

“…These are orchestrated by multiple signaling pathways, including PDGF/PDGFR (Hellstrom et al, 1999), TGF (Majack, 1987;Battegay et al, 1990;Nishishita and Lin, 2004), angiopoietin 1 (Angpt1)-Tie2 (Fukuhara et al, 2008;Saharinen et al, 2008) and BMP (El-Bizri et al, 2008;Spiekerkoetter et al, 2009;Bai et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Msx genes define a population of mural cell precursors required for head blood vessel maturation

et al. 2011

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SUMMARYVessels are primarily formed from an inner endothelial layer that is secondarily covered by mural cells, namely vascular smooth muscle cells (VSMCs) CreERT2 allele, we demonstrated by lineage tracing that the primary defect lies in a population of VSMC precursors. The abnormal phenotype that ensues is a consequence of impaired BMP signaling in the VSMC precursors that leads to downregulation of the metalloprotease 2 (Mmp2) and Mmp9 genes, which are essential for cell migration and integration into the mural layer. Improper coverage by VSMCs secondarily leads to incomplete maturation of the endothelial layer. Our results demonstrate that both Msx1 and Msx2 are required for the recruitment of a population of neural crest-derived VSMCs.

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Section: Research Articlesupporting

confidence: 90%

Section: Proper Bmp Signaling In Head Vsmcs Depends On Msx Genesmentioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Msx genes define a population of mural cell precursors required for head blood vessel maturation

et al. 2011

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“…Gelatin zymography, immunohistochemistry, and immunocytofluorescent staining were performed as described previously. 13,14,17 Quantification of pericyte number has been determined by counting all 3G5-positive (3G5 + ) cells into either the media or the adventitia of the vessels. Quantification by levels of fluorescence intensity or distances between 3G5 + cells and the vessel lumen have been excluded.…”

mentioning

confidence: 99%

Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension

et al. 2014

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P ulmonary arterial hypertension (PAH) is a rapidly progressive disease characterized by obstructive remodeling of distal pulmonary arteries (<500 μm), leading to a progressive elevation in pulmonary vascular resistance and subsequent right heart failure and death. There is currently no cure for PAH, which has a very poor prognosis (mean survival of 2.8 years).1 It is well known that pulmonary arteries display complex structural and functional changes in PAH and that pulmonary endothelial cell (EC) dysfunction plays a crucial role in the disease progression. Despite an increased knowledge in the past years about PAH pathobiological cellular and molecular mechanisms, we still do not know what initiates this disease and its characteristic pulmonary vascular remodeling. Editorial see p 1545 Clinical Perspective on p 1597Pericytes are central regulators of vascular development, stabilization, maturation, and remodeling, modulating EC Background-Pericytes and their crosstalk with endothelial cells are critical for the development of a functional microvasculature and vascular remodeling. It is also known that pulmonary endothelial dysfunction is intertwined with the initiation and progression of pulmonary arterial hypertension (PAH). We hypothesized that pulmonary endothelial dysfunction, characterized by abnormal fibroblast growth factor-2 and interleukin-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening. Methods and Results-In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries compared with controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH endothelial cells compared with conditioned media from control cells. Importantly, by using an anti-fibroblast growth factor-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti-interleukin-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both fibroblast growth factor-2 and interleukin-6 administration increased pericyte coverage. Finally, using idiopathic PAH human and NG2DsRedBAC mouse lung tissues, we demonstrated that this increased pericyte coverage contributes to pulmonary vascular remodeling as a source of smooth muscle-like cells. Furthermore, we found that transforming growth factor-β, in contrast to fibroblast growth factor-2 and interleukin-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells. Conclusions-To the best of our knowledge, this is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We also show that this phenomenon is directly linked with pulmonary endothelial dysfunction. 10 In particular, pericytes that are found along arterioles and capillaries express different degrees...

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Targeting of Mesenchymal Stromal Cells by Cre-Recombinase Transgenes Commonly Used to Target Osteoblast Lineage Cells

Zhang

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2016

Journal of Bone and Mineral Research

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The targeting specificity of tissue-specific Cre-recombinase transgenes is a key to interpreting phenotypes associated with their use. The Ocn-Cre and Dmp1-Cre transgenes are widely used to target osteoblasts and osteocytes, respectively. Here, we used high-resolution microscopy of bone sections and flow cytometry to carefully define the targeting specificity of these transgenes. These transgenes were crossed with Cxcl12gfp mice to identify Cxcl12-abundant reticular (CAR) cells, which are a perivascular mesenchymal stromal population implicated in hematopoietic stem/progenitor cell maintenance. We show that in addition to osteoblasts, Ocn-Cre targets a majority of CAR cells and arteriolar pericytes. Surprisingly, Dmp1-Cre also targets a subset of CAR cells, in which expression of osteoblast-lineage genes is enriched. Finally, we introduce a new tissue-specific Cre-recombinase, Tagln-Cre, which efficiently targets osteoblasts, a majority of CAR cells, and both venous sinusoidal and arteriolar pericytes. These data show that Ocn-Cre and Dmp1-Cre target broader stromal cell populations than previously appreciated and may aid in the design of future studies. Moreover, these data highlight the heterogeneity of mesenchymal stromal cells in the bone marrow and provide tools to interrogate this heterogeneity.

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SM22α-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis

Cited by 60 publications

References 59 publications

Msx genes define a population of mural cell precursors required for head blood vessel maturation

Msx genes define a population of mural cell precursors required for head blood vessel maturation

Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension

Targeting of Mesenchymal Stromal Cells by Cre-Recombinase Transgenes Commonly Used to Target Osteoblast Lineage Cells

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