Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets

Su Li Cheng, Abraham Behrmann, Jian Su Shao, Bindu Ramachandran, Karen Krchma, Yoanna Bello Arredondo, Attila Kovacs, Megan Mead, Robert Maxson, Dwight A. Towler

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4326-4337
Number of pages12
JournalDiabetes
Volume63
Issue number12
DOIs
StatePublished - Jan 1 2014

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Vascular Stiffness
Myofibroblasts
Adventitia
Blood Vessels
Diet
Hedgehogs
Arteriosclerosis
Pulse Wave Analysis
Gene Deletion
High Fat Diet
RNA Interference
Hyperlipidemias
Vascular Smooth Muscle
Hyperglycemia
Smooth Muscle Myocytes
Alkaline Phosphatase
Blood Glucose
Fasting
Obesity
Calcium

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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; Arredondo, Yoanna Bello; Kovacs, Attila; Mead, Megan; Maxson, Robert; Towler, Dwight A.

In: Diabetes, Vol. 63, No. 12, 01.01.2014, p. 4326-4337.

Research output: Contribution to journalArticle

Cheng, SL, Behrmann, A, Shao, JS, Ramachandran, B, Krchma, K, Arredondo, YB, Kovacs, A, Mead, M, Maxson, R & Towler, DA 2014, 'Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets', Diabetes, vol. 63, no. 12, pp. 4326-4337. https://doi.org/10.2337/db14-0326
Cheng, Su Li ; Behrmann, Abraham ; Shao, Jian Su ; Ramachandran, Bindu ; Krchma, Karen ; Arredondo, Yoanna Bello ; 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. In: Diabetes. 2014 ; Vol. 63, No. 12. pp. 4326-4337.
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abstract = "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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AU - Shao, Jian Su

AU - Ramachandran, Bindu

AU - Krchma, Karen

AU - Arredondo, Yoanna Bello

AU - Kovacs, Attila

AU - Mead, Megan

AU - Maxson, Robert

AU - Towler, Dwight A.

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N2 - 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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