Expansive Vascular Remodeling and Increased Vascular Calcification Response to Cholecalciferol in a Murine Model of Obesity and Insulin Resistance

Author(s)

Carmo, Luciana S. ^{[1, 2]} ; Burdmann, Emmanuel A. ^[1] ; Fessel, Melissa R. ^[2] ; Almeida, Youri E. ^[2] ; Pescatore, Luciana A. ^[2] ; Farias-Silva, Elisangela ^[2] ; Gamarra, Lionel F. ^[2] ; Lopes, Gabriel H. ^[2] ; Aloia, Thiago P. A. ^[2] ; Liberman, Marcel ^{[2, 3]}

Affiliation

^[1] Univ Sao Paulo, Sch Med, Div Nephrol, LIM 12, Sao Paulo - Brazil

^[2] Hosp Israelita Albert Einstein, Dept IIEP Res & Teaching Inst, Ave Albert Einstein 627, Floor 2SS Morumbi, BR-05651901 Sao Paulo, SP - Brazil

^[3] Hosp Israelita Albert Einstein, Dept Crit Care Med & Cardiol, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY; v. 39, n. 2, p. 200-211, FEB 2019.
• Web of Science Citations: 4

Abstract

Objective- We hypothesized that ob/ob mice develop expansive vascular remodeling associated with calcification. Approach and Results- We quantified and investigated mechanisms of vascular remodeling and vascular calcification in ob/ob mice after vitamin D-3(VD) stimulation or PBS (control), compared with C57BL/6 mice. Both ob/ob (OBVD {[}VD-treated ob/ob mice]) and C57BL/6 (C57VD {[}VD-treated C57BL/6 mice]) received 8x10(3) IU/day of intraperitoneal VD for 14 days. Control ob/ob (OBCT {[}PBS-treated ob/ob mice]) and C57BL/6 (C57CT {[}PBS-treated C57BL/6 mice]) received intraperitoneal PBS for 14 days. Hypervitaminosis D increased the external and internal elastic length in aortae from OBVD, resulting in increased total vascular area and lumen vascular area, respectively, which characterizes expansive vascular remodeling. OBVD decreased the aortic wall thickness, resulting in hypotrophic vascular remodeling. We demonstrated increased collagen deposition, elastolysis, and calcification in aortae from OBVD. Our results showed a positive correlation between expansive vascular remodeling and vascular calcification in OBVD. We demonstrated increased serum calcium levels, augmented Bmp (bone morphogenetic protein)-2 and osteochondrogenic proteins expression in OBVD aortae. Furthermore, aortae from OBVD increased oxidative stress, coincidently with augmented in situ MMP (matrix metalloproteinase) activity and exhibited no VDR (VD receptor) inhibition after VD. Conclusions- Our data provide evidence that obese and insulin-resistant mice (ob/ob) developed expansive hypotrophic vascular remodeling correlated directly with increased vascular calcification after chronic VD stimulation. Positive hypotrophic vascular remodeling and vascular calcification in this mouse model is possibly mediated by the convergence of absence VDR downregulation after VD stimulation, increased reactive oxygen species generation, and MMP activation. (AU)

• FAPESP's process: 13/09652-0 - Mechanisms of excentric remodeling associated with vascular calcification in obesity and insulin resistance
• Grantee: Luciana Simao Do Carmo
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/09611-2 - Mechanisms of excentric remodeling associated with vascular calcification in obesity and insulin resistance
• Grantee: Marcel Liberman
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/25923-0 - Modulation of vascular calcification by protein disulfide isomerase: study on a new transgenic mouse model
• Grantee: Luciana Pescatore Alves
• Support Opportunities: Scholarships in Brazil - Post-Doctoral