BMP-2 and-4 produced by vascular smooth muscle cells from atherosclerotic lesions induce monocyte chemotaxis through direct BMPRII activation

Author(s)

Simoes Sato, Alex Yuri ^{[1, 2]} ; Bub, Guilherme Linhares ^{[1, 2]} ; Campos, Alexandre Holthausen ^{[1, 2]}

Affiliation

^[1] Hosp Israelita Albert Einstein, Sao Paulo - Brazil

^[2] Ctr Pesquisa Expt, BR-05651901 Sao Paulo - Brazil

• Document type: Journal article
• Source: ATHEROSCLEROSIS; v. 235, n. 1, p. 45-55, JUL 2014.
• Web of Science Citations: 16

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. Methods and 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 Apo / 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. Conclusion: 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. (C) 2014 Elsevier Ireland Ltd. All rights reserved. (AU)

• FAPESP's process: 09/09432-5 - In vitro and in vivo analysis on the role of gremlin, a TGF-beta/BMP pathway antagonist, on the development of atherosclerosis in ApoE knockout mice: a study on vascular smooth muscle cell phenotype.
• Grantee: Alexandre Holthausen Campos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/00410-9 - In vitro and in vivo analysis on the role of gremlin, a TGF-beta/BMP pathway antagonist, on the development of atherosclerosis in ApoE knockout mice: a study on vascular smooth muscle cell phenotype.
• Grantee: Alex Yuri Simões Sato
• Support Opportunities: Scholarships in Brazil - Post-Doctoral