Vascular remodeling is a complex process that plays a central role in many common diseases, including hypertension and atherosclerosis. Remodeling processes such as matrix synthesis and degradation are regulated not only by cytokines and other methods of biochemical communication, but by the powerful influence of physical forces as well. The central theme of this project is that mechanical forces modulate the remodeling activities of vascular smooth muscle cells, the principal source of extracellular matrix in the diseased artery. Understanding how mechanical signals modify vascular smooth muscle cell remodeling activities may provide future strategies for prevention of acute vascular events such as plaque rupture and myocardial infarction. In these experiments, we will use cultured human aortic smooth muscle cells (HSMCs) and a unique method of applying a biaxially uniform strain to cultured cells.
The Specific Aims are: 1) To characterize induction of molecular and cellular responses of HSMCs to mechanical stimuli. Vascular smooth muscle cells are exposed to a wide variety of mechanical stimuli, including static stresses of mean arterial pressure, dynamic stresses of the pulse wave, and sometimes single, transient, high stresses, such as during an angioplasty procedure. The investigators will compare the influence of static and dynamic stimuli on induction of immediate-early activation genes in HSMCs, including genes that are likely to be mechanoresponsive. In addition, they will characterize the influence of varying mechanical stimuli on other cellular responses that may influence vascular remodeling, 2) To determine the influence of mechanical stimuli on the secretion and activation of matrix metalloproteinases. Cultured HSMCs have a system of matrix metalloproteinase synthesis and activation which is regulated both by cytokines and by plasmin. One way that mechanical forces can influence vascular remodeling is to modulate this matrix degradation pathway. They will test the hypothesis that mechanical stimuli regulate this coordinated matrix degradation system of HSMCs at several potential steps, and 3) To determine the role of specific integrins in the transduction of mechanical signals to vascular smooth muscle cells. Integrins are heterodimeric cell surface receptors that can participate in transducing mechanical signals from the extracellular matrix. These experiments will evaluate integrins as mediators of mechanotransduction events in HSMCs, focusing on the B1 integrins.
