Gremlin-1 potentiates the dedifferentiation of VSMC in early stages of atherosclerosis

Author(s)

de Barros, Renata Silverio ^{[1, 2]} ; Dias, Grazielle Suhett ^{[1, 2]} ; do Rosario, Ana Paula ^{[1, 2]} ; Paladino, Fernanda Vieira ^{[1, 2]} ; Lopes, Gabriel Herculano ^[1] ; Campos, Alexandre Holthausen ^{[1, 2]}

Affiliation

^[1] Hosp Israelita Albert Einstein, Ave Albert Einstein 627, 2S, Bloco A, BR-05651901 Sao Paulo, SP - Brazil

^[2] Ctr Pesquisa Expt, Av Albert Einstein 627, 2S, Bloco A, BR-05651901 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: DIFFERENTIATION; v. 109, p. 28-33, SEP-OCT 2019.
• Web of Science Citations: 0

Abstract

Vascular smooth muscle cells (VSMC) are highly specialized, and exhibit a contractile phenotype when mature and fully differentiated, being responsible for vessel homeostasis and blood pressure control. In response to proatherogenic stimuli VSMC alter their state of differentiation, increase proliferation and migration, resulting in SMC phenotypes ranging from contractile to synthetic. This variability is observed in cell morphology and expression level of marker genes for differentiation status. There is growing evidence that bone morphogenetic protein (BMP) signaling is involved in vascular diseases, including atherosclerosis. Here, we evaluated in vitro the role of specific agonists/antagonists belonging to the BMP pathway on dedifferentiation of VSMC harvested during early stages of atherosclerosis. Results: Comparing primary VSMC isolated from aortas of susceptible ApoE-/- animals fed 8 weeks of western diet with their littermate controls fed usual diet, we observed that recombinant BMP4 was able to reduce SM22-alpha and alpha actin gene expression indicating dedifferentiation was under way. Unexpectedly, treatment with recombinant Gremlin-1, a known BMP antagonist, also reduced 4-6.5 folds gene expression of SM22-alpha, alpha-actin and, calponin, exclusively in VSMC from ApoE-/- animals, independently on the diet consumed. Conclusion: Our data show that BMP4 is capable of modulating of SM22-alpha and alpha actin gene expression, indicative of cell dedifferentiation in VSMC. Additionally, we report for first time that Gremlin-1 acts independently of the BMP pathway and selectively on VSMC from susceptible animals, reducing the expression of all genes evaluated. (AU)

• FAPESP's process: 14/16461-0 - DEDIFFERENTIATION OF VASCULAR SMOOTH MUSCLE CELLS IN THE DEVELOPMENT OF ATHEROSCLEROSIS - THE ROLE OF BMP SIGNALING
• Grantee: Renata Silvério de Barros
• Support Opportunities: Scholarships in Brazil - Master