title: BMP-2 and -4 produced by vascular smooth muscle cells from atherosclerotic lesions induce monocyte chemotaxis through direct BMPRII activation.
abstract: OBJECTIVE
  Monocytes and macrophages, together with vascular smooth muscle cells (VSMCs), play key roles at all stages of atherogenesis. There is also growing evidence that BMP signaling is involved in vascular diseases, including atherosclerosis. Here we evaluate the role played by the BMP agonist/antagonist axis in monocyte recruitment during atherogenesis.
  
  
  RESULTS
  Using ApoE-/- mice and BMPs, Gremlin and BMPRII siRNAs we show that BMPs (2 and 4) and their antagonist Gremlin are co-expressed in murine and human atherosclerotic vessels. Additionally, those genes are co-expressed and upregulated in cultured vascular smooth muscle cells early in atherosclerosis formation in ApoE-/- mice. Furthermore, we demonstrate that BMP-2 and -4 produced in atherosclerotic VSMCs promote, whereas Gremlin inhibits, monocyte chemoattraction. Finally, we demonstrate that chemotaxis induction occurs through direct BMP receptor II (BMPRII) activation.
  
  
  CONCLUSIONS
  These findings suggest that the balance between BMPs (2 and 4) and Gremlin levels modulate crosstalk processes between vascular and immune cells and ultimately the homeostasis in normal vasculature. They also indicate that under pro-atherogenic conditions, BMP signaling prevails, favoring monocyte recruitment and inflammation. Manipulation of BMP signaling may enable the identification of novel molecular approaches for preventing, stabilizing, and reverting atherosclerosis.
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil; Centro de Pesquisa Experimental, Av Albert Einstein, 627 - Morumbi, 2S/Bloco A, São Paulo, SP CEP 05651-901, Brazil. Electronic address: alexsimoessato@gmail.com.
authors.forename: Alex Yuri
authors.initials: AY
authors.lastname: Simões Sato
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil; Centro de Pesquisa Experimental, Av Albert Einstein, 627 - Morumbi, 2S/Bloco A, São Paulo, SP CEP 05651-901, Brazil. Electronic address: guilherme.bub@einstein.br.
authors.forename: Guilherme Linhares
authors.initials: GL
authors.lastname: Bub
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil; Centro de Pesquisa Experimental, Av Albert Einstein, 627 - Morumbi, 2S/Bloco A, São Paulo, SP CEP 05651-901, Brazil. Electronic address: holthausen@einstein.br.
authors.forename: Alexandre Holthausen
authors.initials: AH
authors.lastname: Campos
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism*; D002465:Cell Movement; D002633:Chemotaxis; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C498218:BMPR2 protein, human; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: Atherosclerosis; BMP; Chemotaxis; Gremlin; Inflammation; Monocyte; Smooth muscle cell