title: Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets.
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.
authors: Sanford-Burnham Medical Research Institute, Orlando, FL.
authors: Su-Li
authors: SL
authors: Cheng
authors: Sanford-Burnham Medical Research Institute, Orlando, FL.
authors: Abraham
authors: A
authors: Behrmann
authors: MD Anderson Cancer Center, Houston, TX.
authors: Jian-Su
authors: JS
authors: Shao
authors: Sanford-Burnham Medical Research Institute, Orlando, FL.
authors: Bindu
authors: B
authors: Ramachandran
authors: Sanford-Burnham Medical Research Institute, Orlando, FL.
authors: Karen
authors: K
authors: Krchma
authors: Sanford-Burnham Medical Research Institute, Orlando, FL.
authors: Yoanna
authors: Y
authors: Bello Arredondo
authors: Washington University in St. Louis, St. Louis, MO.
authors: Attila
authors: A
authors: Kovacs
authors: Sanford-Burnham Medical Research Institute, Orlando, FL.
authors: Megan
authors: M
authors: Mead
authors: Norris Cancer Center, University of Southern California, Los Angeles, CA.
authors: Robert
authors: R
authors: Maxson
authors: Sanford-Burnham Medical Research Institute, Orlando, FL Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL dtowler@sanfordburnham.org.
authors: Dwight A
authors: DA
authors: Towler
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001011:Aorta / Q000378:metabolism*; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat; D017353:Gene Deletion; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D051957:MSX1 Transcription Factor / Q000235:genetics*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D061205:Vascular Calcification / Q000235:genetics* / Q000378:metabolism; D059289:Vascular Stiffness / Q000235:genetics*; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein; D051154:Wnt2 Protein / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C074650:Ly6a protein, mouse; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; D008565:Membrane Proteins; C484084:Msx1 protein, mouse; D011973:Receptors, LDL; C465570:Shh protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051154:Wnt2 Protein; C438615:Wnt5a protein, mouse