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Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets

When fed high-fat diets, male LDLR(−/−) mice develop obesity, hyperlipidemia, hyperglycemia, and arteriosclerotic calcification. An osteogenic Msx-Wnt regulatory program is concomitantly upregulated in the vasculature. To better understand the mechanisms of diabetic arteriosclerosis, we generated SM...

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Autores principales: Cheng, Su-Li, Behrmann, Abraham, Shao, Jian-Su, Ramachandran, Bindu, Krchma, Karen, Bello Arredondo, Yoanna, Kovacs, Attila, Mead, Megan, Maxson, Robert, Towler, Dwight A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237989/
https://www.ncbi.nlm.nih.gov/pubmed/25056439
http://dx.doi.org/10.2337/db14-0326
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author Cheng, Su-Li
Behrmann, Abraham
Shao, Jian-Su
Ramachandran, Bindu
Krchma, Karen
Bello Arredondo, Yoanna
Kovacs, Attila
Mead, Megan
Maxson, Robert
Towler, Dwight A.
author_facet Cheng, Su-Li
Behrmann, Abraham
Shao, Jian-Su
Ramachandran, Bindu
Krchma, Karen
Bello Arredondo, Yoanna
Kovacs, Attila
Mead, Megan
Maxson, Robert
Towler, Dwight A.
author_sort Cheng, Su-Li
collection PubMed
description When fed high-fat diets, male LDLR(−/−) mice develop obesity, hyperlipidemia, hyperglycemia, and arteriosclerotic calcification. An osteogenic Msx-Wnt regulatory program is concomitantly upregulated in the vasculature. To better understand the mechanisms of diabetic arteriosclerosis, we generated SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) mice, assessing the impact of Msx1+Msx2 gene deletion in vascular myofibroblast and smooth muscle cells. Aortic Msx2 and Msx1 were decreased by 95% and 34% in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) animals versus Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) controls, respectively. Aortic calcium was reduced by 31%, and pulse wave velocity, an index of stiffness, was decreased in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) mice vs. controls. Fasting blood glucose and lipids did not differ, yet SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) siblings became more obese. Aortic adventitial myofibroblasts from SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) mice exhibited reduced osteogenic gene expression and mineralizing potential with concomitant reduction in multiple Wnt genes. Sonic hedgehog (Shh) and Sca1, markers of aortic osteogenic progenitors, were also reduced, paralleling a 78% reduction in alkaline phosphatase (TNAP)–positive adventitial myofibroblasts. RNA interference revealed that although Msx1+Msx2 supports TNAP and Wnt7b expression, Msx1 selectively maintains Shh and Msx2 sustains Wnt2, Wnt5a, and Sca1 expression in aortic adventitial myofibroblast cultures. Thus, Msx1 and Msx2 support vascular mineralization by directing the osteogenic programming of aortic progenitors in diabetic arteriosclerosis.
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spelling pubmed-42379892015-12-01 Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets Cheng, Su-Li Behrmann, Abraham Shao, Jian-Su Ramachandran, Bindu Krchma, Karen Bello Arredondo, Yoanna Kovacs, Attila Mead, Megan Maxson, Robert Towler, Dwight A. Diabetes Complications When fed high-fat diets, male LDLR(−/−) mice develop obesity, hyperlipidemia, hyperglycemia, and arteriosclerotic calcification. An osteogenic Msx-Wnt regulatory program is concomitantly upregulated in the vasculature. To better understand the mechanisms of diabetic arteriosclerosis, we generated SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) mice, assessing the impact of Msx1+Msx2 gene deletion in vascular myofibroblast and smooth muscle cells. Aortic Msx2 and Msx1 were decreased by 95% and 34% in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) animals versus Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) controls, respectively. Aortic calcium was reduced by 31%, and pulse wave velocity, an index of stiffness, was decreased in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) mice vs. controls. Fasting blood glucose and lipids did not differ, yet SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) siblings became more obese. Aortic adventitial myofibroblasts from SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR(−/−) mice exhibited reduced osteogenic gene expression and mineralizing potential with concomitant reduction in multiple Wnt genes. Sonic hedgehog (Shh) and Sca1, markers of aortic osteogenic progenitors, were also reduced, paralleling a 78% reduction in alkaline phosphatase (TNAP)–positive adventitial myofibroblasts. RNA interference revealed that although Msx1+Msx2 supports TNAP and Wnt7b expression, Msx1 selectively maintains Shh and Msx2 sustains Wnt2, Wnt5a, and Sca1 expression in aortic adventitial myofibroblast cultures. Thus, Msx1 and Msx2 support vascular mineralization by directing the osteogenic programming of aortic progenitors in diabetic arteriosclerosis. American Diabetes Association 2014-12 2014-11-13 /pmc/articles/PMC4237989/ /pubmed/25056439 http://dx.doi.org/10.2337/db14-0326 Text en © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Complications
Cheng, Su-Li
Behrmann, Abraham
Shao, Jian-Su
Ramachandran, Bindu
Krchma, Karen
Bello Arredondo, Yoanna
Kovacs, Attila
Mead, Megan
Maxson, Robert
Towler, Dwight A.
Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets
title Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets
title_full Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets
title_fullStr Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets
title_full_unstemmed Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets
title_short Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets
title_sort targeted reduction of vascular msx1 and msx2 mitigates arteriosclerotic calcification and aortic stiffness in ldlr-deficient mice fed diabetogenic diets
topic Complications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237989/
https://www.ncbi.nlm.nih.gov/pubmed/25056439
http://dx.doi.org/10.2337/db14-0326
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