REGULATION OF VASCULAR SMOOTH MUSCLE PHENOTYPE BY NOTCH SIGNALING

  REGULATION OF VASCULAR SMOOTH MUSCLE

PHENOTYPE BY NOTCH SIGNALING

By Joshua Michael Boucher

Thesis Advisor: Dr. Lucy Liaw

A Lay Abstract of the Thesis Presented

in Partial Fulfillment of the Requirements for the

Degree of Doctor of Philosophy

(in cell and molecular biology)

April, 2013

Image was taken by the author-2013

            Cardiovascular disease claims the lives of approximately 2,150 Americans each day and remains the leading cause of death among men and women in this country. Vascular smooth muscle cells are an important cell type required for normal vascular function because they provide tone to the vessel and help regulate blood pressure. Blood vessel damage due to poor diet, smoking and genetic predisposition can promote build-up of lipid in the vessel wall, high blood pressure, and decreased blood flow. These changes that occur in vascular disease are often accompanied at the cellular level by abnormal smooth muscle cell growth and movement with the blood vessel wall. My research focuses on a family of proteins, the Notch family of cell surface receptors, and their role during vascular disease and smooth muscle cell dysfunction.  There are four Notch proteins in humans, and their normal signaling may regulate cardiovascular disease and stroke. However, the role of each of the four receptors has not been well characterized. The goal of this work is to understand the functions of this Notch family in smooth muscle cell behavior in normal and diseased blood vessels. To address this, I  used three strategies: 1) study smooth muscle cells derived from human vessels and test how Notch signaling changes their behavior, 2) use mouse genetic models and vascular surgery to look at disease processes (example shown in figure above), and 3) characterize Notch signaling components in biopsies of vessels from patients with different types of cardiovascular disease. The results of my studies show that the Notch2 and the Notch3 receptor have unique functions, and each stimulates novel gene targets that mediate its function in smooth muscle cells. These results are significant in understanding the cellular and molecular basis of smooth muscle function and their contribution to vascular diseases.