Our research is devoted to investigation of the events in cells inside the blood vessel walls, which cause cardiovascular disorders, the main cause of death in the developed world. A thin layer of muscle inside the vessel wall governs blood pressure and blood flow along the vessels. This layer consists of smooth muscle cells that contract and relax in response to hormones and stimuli from nerves. Contraction and relaxation of vascular smooth muscle cells are regulated by complex mechanisms inside cells that depend on ion exchange, cellular architecture, and activity of intracellular proteins. Calcium entering the cell through special protein channels plays a central role in regulation of vascular function. We study which proteins regulate calcium influx in vascular cells, and how calcium distribution inside the cell interplays with intracellular structure to regulate vasoconstriction. We also study how diseases such as diabetes or Marfan syndrome affect these orchestrated intracellular mechanisms.
Vascular dysfunction in Marfan syndrome
Marfan syndrome (MFS) is an autosomal dominant disorder with mutations in FBN1 gene encoding fibillin-1, the main component of the extracellular microfibrils that is important for formation of elastic fibers. Over 90% of mortality is related to aortic complications in the form of aortic dilatation and rupture. Both smooth muscle and endothelial cells as well as extracellular matrix components could be impaired in MFS. In our project, we use a genetic mouse model of MFS to investigate the cellular mechanisms of the age-dependent disease progression. We intend to characterize the distensibility and elasticity of aortae in vitro, pathologic mechanisms in endothelial and smooth muscle cell signalling, calcium patterns, vessel remodelling, extracellular matrix integrity, cellular ultrastructure, and cell-to-cell interactions. We will monitor disease progression and pathogenesis in the microcirculation in vivo. In addition, we plan to monitor the response to medical therapy. We believe that the study of the biophysical properties and the cellular mechanisms of Marfan syndrome will give new pharmacological targets for treatment of this disease.
Cellular mechanisms of vascular dysfunction in human diabetes
Cardiovascular disorders in diabetes are caused by alterations in cellular mechanisms in endothelial and smooth muscle cells. Unfortunately, at the present time, there is neither the complete understanding of the cellular mechanisms in diabetes, especially in human type 1 (juvenile) and type 2 diabetes, nor specific treatment for cardiovascular disease in patients with diabetes. We study the effect of high glucose concentrations on the human endothelial and smooth muscle cell function (as a model of juvenile diabetes), and changes in signaling pathways in human vascular cells which lead to augmented vasoconstriction and enhanced proliferation. We also investigate spatial and temporal calcium patterns in diabetic vascular cells, alterations in the expression and activity of calcium channels, changes in the cell architecture and extracellular matrix, which contribute to accelerated development of atherosclerosis. This research leads us towards a comprehensive understanding of the cellular mechanisms underlying cardiovascular disease in diabetes, identifying biomarkers and to developing specific therapy for cardiovascular disease and post-surgical care in diabetic patients.
Calcium oscillations in vascular smooth muscle
Ca2+ is a central messenger of smooth muscle function, which regulates both vascular tone and the processes of proliferation, migration and apoptosis. Aberrations in these functions are causally involved in vascular diseases, which are the main causes of death in the developed world. The key to selective Ca2+ regulation of multiple functions lies in the cell's ability to create Ca2+ signals possessing specific temporal and spatial characteristics, which encode differential regulatory information. Ca2+ oscillations are an integral part of "site and function-specific" Ca2+ signaling in smooth muscle cells. These Ca2+ fluctuations are generated by ion channels, exchangers and pumps in the plasma membrane, sarcoplasmic reticulum, and mitochondria, which are strategically clustered in microdomains. In the current project, we study how cell function in norm, neonatal development, aging and disease is related to the temporal and spatial intracellular calcium pattern, the expression and activity of calcium channels, their spatial organization and cellular ultrastructure.Grants
CIHR Operating Grant, Cellular Mechanisms Underlying Vascular Dysfunction & Aortic Aneurysm in Marfan syndrome, 2011Research Group Members
Zhi Lin Lee, Volunteer