Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets
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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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Specific genetic modulation of VSMC osteochondrogenesis in vivo leads to altered calcification in models of atherosclerosis.
“Furthermore, specific genetic modulation of VSMC osteochondrogenesis in vivo leads to altered calcification in models of atherosclerosis 160-162 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [160]
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Zhang, X., Li, Y., Yang, P., Liu, X., Lu, L., Chen, Y., Zhong, X., Li, Z., Liu, H., Ou, C., et al. (2020) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.313414 · Cited by 291 · see citing works
- Authors
- Cheng, S.-L., Behrmann, A., Shao, J.-S., Ramachandran, B., Krchma, K., Bello Arredondo, Y., Kovacs, A., Mead, M., Maxson, R., & Towler, D. A.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- The University of Texas MD Anderson Cancer Center (US)
- Sanford-Burnham Medical Research Institute, Orlando, FL
- Washington University in St. Louis, St. Louis, MO
- University of Southern California (US)
- Corresponding author
- Towler, Dwight A.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2014-11-13
- Volume
- 63
- Issue
- 12
- Pages
- 4326-4337
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4237989
- OpenAlex
- W2075023944
- Cited by
- 77
- References
- 52
- Citations by year
- 2026: 1 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 3 · 2020: 15 · 2019: 9 · 2018: 7 · 2017: 6 · 2016: 9 · 2015: 6 · 2014: 1
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL114806, R01HL081138, HL 81138, HL-69229, R01HL069229)
- National Institute of Dental and Craniofacial Research (R01DE016320, DE016320)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- MSX1, Msx2, vascular calcification, Ldlr-deficient mice, high-fat diet, aortic stiffness, pulse wave velocity, Wnt signaling, Sonic hedgehog, spinocerebellar ataxia type 1, tissue-nonspecific alkaline phosphatase, Wnt7b, Wnt2, Wnt5a, gene deletion
- MeSH terms
- Wnt-5a Protein, Animals, Antigens, Ly, Aorta, Arteriosclerosis, Cells, Cultured, Diabetes Mellitus, Experimental, Membrane Proteins, Osteogenesis, Receptors, LDL, Gene Deletion, Mice, Knockout, Homeodomain Proteins, Gene Expression Profiling, Myocytes, Smooth Muscle, Wnt Proteins, Wnt2 Protein, Mice, MSX1 Transcription Factor, Hedgehog Proteins, Myofibroblasts, Vascular Stiffness, Diet, High-Fat, Vascular Calcification
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