Myron Cybulsky

Dr. Cybulsky received a M.D. degree in 1982 from the University of Toronto and completed residency training in Anatomic Pathology at this institution in 1986. His research training included quantification of acute inflammation and investigation of relevant mediators with Dr. Henry Movat at the University of Toronto and a research fellowship in vascular biology with Dr. Michael Gimbrone, Jr., at Harvard Medical School (1987-1991). 

From 1991, he was a member of the faculty in the Departments of Pathology at the Brigham and Women’s Hospital and Harvard Medical School, where he ran a NIH-funded basic research laboratory. 

In 1996, Dr. Cybulsky was recruited to the University of Toronto, where he currently is a Professor of Laboratory Medicine and Pathobiology. His laboratory is at the Toronto General Research Institute, where he is a Senior Scientist. He is also a Staff Pathologist and consultant in cardiovascular pathology at the University Health Network. 

Dr. Cybulsky’s research focuses on regional differences in the arterial intima that predispose the artery wall to atherogenesis and on cellular events that occur in early atherosclerotic lesions such as monocyte recruitment and proliferation of intimal myeloid cells.  He also studies the functions of alpha-4 integrins in leukocyte adhesion to VCAM-1 and recruitment to sites of inflammation. This research may lead to new insights into the cellular and molecular mechanisms underlying the onset of atherosclerosis and inflammation.   

Research synopsis

Our research focuses on initiation of atherosclerosis, specifically regional differences in the normal arterial intima that predispose it to atherogenesis, intimal dendritic cells and monocyte recruitment and myeloid cell proliferation in early lesions. Another focus is functions of alpha-4 integrins in leukocyte recruitment to sites of inflammation.

The recruitment of white blood cells (leukocytes) from the blood into tissues is a key process in inflammation and contributes to atherosclerosis, autoimmune conditions and rejection of transplanted organs. Monocytes are a subtype of leukocytes, and they play a critical role in atherosclerosis, a disease that results in heart attacks and strokes. Therefore, inhibition of monocyte recruitment can constitute an important therapeutic approach for treatment of atherosclerosis, and understanding mechanisms of monocyte recruitment is critical to achieving this goal. 

Adhesion molecules orchestrate monocyte recruitment. They include monocyte alpha-4 integrins that bind to VCAM-1 on endothelial cells. Endothelial cells line the inner wall of blood vessels. During recruitment, adherent leukocytes experience the force of flowing blood. Leukocytes must develop strong and stable adhesions in order to remain attached to endothelial cells and withstand the detachment forces imparted by flowing blood. 

Our goal is to determine the mechanisms by which leukocytes stabilize their adhesion in flowing blood. We will investigate signaling pathways, including those initiated by alpha-4 integrins, as well as a dynamic skeleton formed by actin molecules, that provides the leukocyte with tensile strength, a structural scaffold and regulates movement.

Dendritic cells (DCs) are a specialized class of white blood cells that are critical to the body’s immune system and are found in the inner artery wall of healthy humans and animals. We found that DCs are particularly abundant in atherosclerosis-predisposed areas of normal mice, and named these cells resident intimal DCs or RIDCs. We also found that when blood cholesterol is high, RIDCs take up lipid and transform into lipid-loaded foam cells, which is the first step in the formation of atherosclerosis. 

Recently, we discovered that RIDCs exit from the normal artery wall after an inflammatory stimulus was injected into the bloodstream. However, lipid accumulation in RIDCs as a result of high blood cholesterol blocks their exit. The goal of our research is to elucidate the mechanisms underlying RIDC exit from normal arteries, and determine how accumulated lipid inhibits it. 

We are investigating the functions of a receptor called CCR7 and molecules called CCL19 and CCL21, which bind to CCR7. We anticipate that information gained from the proposed studies will enable us to overcome the inhibitory mechanisms in lipid-loaded DCs in the future, so that lipid can be removed from the artery wall by exiting lipid-loaded DCs.

Atherosclerosis is a disease caused by risk factors such as elevated levels of LDL-cholesterol and involves the formation of lesions or plaques on the inner portion of the artery wall. As lesions enlarge, they cause narrowing or blockage and loss of blood supply to tissues, resulting in a heart attack or stroke. In some regions, the inner layer of arteries contains white blood cells (leukocytes).

At the early stages of lesion formation, leukocytes take up lipid and become foam cells, undergo cell division (proliferation) and there is excessive leukocyte entry into the artery wall (recruitment). The goal of our research is to gain a better understanding of the cellular and molecular basis of lesion formation during the development of atherosclerosis. Our recent success in tracking cell proliferation of leukocytes as well as leukocyte recruitment from blood into the aorta revealed that both processes take place in early stages of lesion formation.

We will utilize this approach to determine the roles played by leukocyte recruitment and proliferation and the relationship between these events during distinct stages of lesion formation. We will also monitor the extent of cell death at each stage, since cell survival versus death influences the outcome of lesions. The contribution of specific molecules critical for leukocyte recruitment and proliferation will be explored. We will also investigate the roles of a newly emerging family of proteins, called Nod-like receptors (NLR) that mediate the response of cells to signals that are sensed as danger. 

Selected publications

Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251:788-791, 1991.

Gurtner GC, Davis V, McCoy MJ, Li H, Sharpe A, Cybulsky MI. Targeted disruption of the murine VCAM1 gene: essential role for VCAM-1 in chorioallantoic fusion and placentation. Genes & Development 9:1-14, 1995.

Lichtman AH, Clinton SK, Iiyama K, Connelly PW, Libby P, Cybulsky MI. Hyperlipidemia and atheroslcerotic lesion development in LDL receptor-deficient mice fed defined semipurified diets with and without cholate. Arterioscler Thromb Vasc Biol 19:1938-1944, 1999.

Iiyama K, Hajra L, Iiyama M, Li H, DiChiara M, Medoff BD, Cybulsky MI. Patterns of VCAM-1 and ICAM-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res 1999; 85:199-207.

Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky M. The NF-κB signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci (USA) 2000; 97:9052-9057.

Chan JR, Hyduk SJ, Cybulsky MI. Chemoattractants induce a rapid and transient upregulation of monocyte α4 integrin affinity for VCAM-1, which mediates arrest - an early step in the process of emigration. J Exp Med 2001; 193;1149-58.

Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, Davis V, Gutierrez-Ramos J-C, Milstone DS. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 2001; 107;1255-1262.

Dansky HM, Barlow CB, Lominska C, Sikes JL, Kao C, Weinsaft J, Cybulsky MI, Smith JD. Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on VCAM-1 gene dosage. Arterioscler Thromb Vasc Biol 2001; 21:1662-1667.

Hyduk SJ, Oh J, Xiao H, Chen M, Cybulsky MI. Paxillin selectively associates with constitutive and chemoattractant-induced high affinity alpha-4/beta-1 integrins: implications for integrin signaling. Blood 2004, 104:2818-2824.

Jongstra-Bilen J, Haidari M, Zhu S-N, Chen M, Guha D, Cybulsky MI. Low-grade inflammation in regions of normal mouse arterial intima predisposed to atherosclerosis. J Exp Med 2006; 203:2073-83.

Hyduk SJ, Chan JR, Duffy ST, Chen M, Peterson MD, Xiao H, Waddell TK, Digby GC, Szaszi K, Kapus A, Cybulsky MI. Phospholipase C, calcium and calmodulin are critical for α4β1 integrin affinity up-regulation and monocyte arrest triggered by chemoattractants. Blood 2007; 109:176-84.

Won D, Zhu S-N, Chen M, Teichert AM, Fish JE, Matouk CC, Bonert M, Ojha M, Marsden PA, Cybulsky MI. Relative reduction of eNOS expression and transcription in atherosclerosis-prone regions of the mouse aorta and in an in vitro model of disturbed flow. Am J Pathol 2007; 171:1691–1704.

Zhu S-N, Chen M, Jongstra-Bilen J, Cybulsky MI.  GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions. J Exp Med 2009; 206:2141-2149.

Paulson KE, Zhu S-N, Chen, M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI.  Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ Res 2010; 106:383-390.

Zhou Y-Q, Zhu S-N, Foster SF, Cybulsky MI, Henkelman RM. Aortic regurgitation dramatically alters the distribution of atherosclerotic lesions and enhances atherogenesis in mice. Arterioscler Thromb Vasc Biol 2010; 30:1181-1188.

Haidari M, Ali M, Gangehei L, Chen M, Zhang W, Cybulsky MI. Increased oxidative stress in atherosclerosis-predisposed regions of the mouse aorta. Life Sci 2010; 87:100-110.

Hyduk SJ, Rullo J, Puig-Cano A, Xiao H, Chen M, Moser M, Cybulsky MI. Talin-1 and kindlin-3 regulate α4β1 integrin-mediated adhesion stabilization, but not GPCR-induced affinity upregulation. J Immunol 2011; 187: 4360-4368.

Rullo J, Becker H, Hyduk SJ, Wong JC, Digby G, Arora PD, Puig-Cano A, Hartwig J, McCulloch CA, Cybulsky MI. Actin polymerization stabilizes α4β1-integrin anchors that mediate monocyte adhesion. J Cell Biol 2012; 127:115-129.

Honours and Awards

LMP Distinguished Service Award (2024)