The overall goal of this research is to understand the etiologic role of macrophage colony-stimulating factor (M-CSF) in atherosclerosis. Accumulating evidence suggests that M-CSF by influencing the recruitment, growth, survival and function of monocyte-macrophages, may contribute importantly to the promotion of atherosclerosis. Supporting this conclusion are this laboratory's recent findings showing that absence of M-CSF in apolipoprotein (apo) E or low density lipoprotein receptor-deficient mice significantly reduces atherosclerosis despite augmented hypercholesterolemia. The mechanism(s) underlying the causal role of M-CSF in atherosclerosis is not known, but may involve specific isoforms of M-CSF whose biological effects are mediated by a single receptor. The overall hypothesis is that augmented expression of tissue associated M-CSF isoforms in response to atherogenic stimuli in the vessel wall and bone marrow plays a critical role in the development of atheromatous lesions. To test aspects of this hypothesis, studies are proposed with the following specific aims: 1) to study the effects of M-CSF deficiency in the vessel wall on the development of arterial lesions by transplanting wild type. bone marrow cells into mice lacking both M-CSF and apoE and to determine by immunological assays which isoforms of M-CSF are expressed by vascular cells in the normal vessel and during atherogenesis in apo-E null mice; 2) to perform in vitro studies using cultured vascular cells from humans and osteopetrotic (op/op) mice to examine the mechanism(s) underlying the M-CSF mediated growth and activation of monocytes and intimal smooth muscle cells; 3) to produce transgenic mice expressing only the mM-CSF isoform on an op/op genetic background and to examine the effects of the mM-CSF on atherogenesis either by feeding the transgenic mice a high fat, high cholesterol diet or by crossing them with apo E-null mice to generate compound mutants expressing mM-CSF on an atherogenic background. These studies may provide new and exciting information that might prove valuable in the rational design of novel therapeutic interventions for atherosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Pathology A Study Section (PTHA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cedars-Sinai Medical Center
Los Angeles
United States
Zip Code
Qiao, Jian-Hua; Mishra, Vivek; Fishbein, Michael C et al. (2015) Multinucleated giant cells in atherosclerotic plaques of human carotid arteries: Identification of osteoclast-like cells and their specific proteins in artery wall. Exp Mol Pathol 99:654-62
Uzui, Hiroyasu; Sinha, Satyesh K; Rajavashisth, Tripathi B (2011) 17?-estradiol inhibits oxidized low-density lipoprotein-induced increase in matrix metalloproteinase-9 expression in human macrophages. J Investig Med 59:1104-8
Neyer, Jonathan; Espinoza, Christian; Luppen, Luppe et al. (2005) A comparison of anion-exchange and steric-exclusion HPLC assays of mouse plasma lipoproteins. J Lipid Res 46:1786-95
Qiao, Jian-Hua; Doherty, Terence M; Fishbein, Michael C et al. (2005) Calcification of the coronary arteries in the absence of atherosclerotic plaque. Mayo Clin Proc 80:807-9
Michelsen, Kathrin S; Wong, Michelle H; Shah, Prediman K et al. (2004) Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U S A 101:10679-84
Doherty, Terence M; Fitzpatrick, Lorraine A; Inoue, Daisuke et al. (2004) Molecular, endocrine, and genetic mechanisms of arterial calcification. Endocr Rev 25:629-72
Finkelstein, Ariel; Hausleiter, Joerg; Doherty, Terence et al. (2004) Intracoronary beta-irradiation enhances balloon-injury-induced tissue factor expression in the porcine injury model. Int J Cardiovasc Intervent 6:20-7
Doherty, Terence M; Fitzpatrick, Lorraine A; Shaheen, Aisha et al. (2004) Genetic determinants of arterial calcification associated with atherosclerosis. Mayo Clin Proc 79:197-210
Doherty, Terence M; Shah, Prediman K; Rajavashisth, Tripathi B (2003) Cellular origins of atherosclerosis: towards ontogenetic endgame? FASEB J 17:592-7
Doherty, Terence M; Asotra, Kamlesh; Fitzpatrick, Lorraine A et al. (2003) Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci U S A 100:11201-6

Showing the most recent 10 out of 15 publications