Dr. George Osol's laboratory is carrying out investigations in three areas of physiology. The first involves mechanotransduction, i.e. trying to understand how physical forces such as pressure are transduced by the cells of the arterial wall into contraction. Earlier studies have led to the elucidation of a dual pathway involving calcium entry through L-type channels, combined with activation of enzyme cascades - most prominently, phospholipase C/Protein kinase C - that alter contractility by affecting smooth muscle calcium sensitivity and thin filament (actin) regulation. Current experiments involve measuring cytosolic calcium in isolated, pressurized cerebral artreries while observing pressure- and agonist-induced changes in lumen diameter.
The second area of research is aimed at understanding the cellular mechanisms that are involved in the marked growth of the uterine circulation during pregnancy. Previous studies have characterized the patterns and extent of arterial growth, and of changes in VEGF mRNA expression and isoform distribution in uterine and placental tissues. Most recently, we have been focusing on venoarterial signal transfer as a mechanism for modulating arterial growth. The concept here is that vasoactive and growth-promoting substances secreted by the placenta pass into the maternal uterine venous circulation. The parallel and proximal arrangement of arteries and veins suggests the possibility of signal transfer across the venous wall. The signals can be used to control arterial tone, and to stimulate remodeling by cellular and matrix mechanisms.
Finally, the third focus of the lab is on estrogen and estrogen-like compounds as they affect endothelial function in small resistance arteries. With the advent of selective estrogen receptor modulators (SERM), such as raloxifene, studies are being carried out to compare the efficacy of SERM compounds to that of estrogen in augmenting endothelial dilator production and secretion. Enhanced production of substances such as nitric oxide or prostacyclin leads to a decrease in arterial tone and peripheral resistance and mean arterial pressure. We postulate that the endothelial mechanims constitute an important component of the cardioprotective actions of estrogen.
The experimental approach is in vitro, specifically, studying small arteries under pressurized, cannulated conditions and observing arterial reactivity with the help of a video-electronic imaging system. Calcium measurement, pharmacological manipulation, and confocal and electron microscopy are employed as adjuncts for understanding the relationship between cellular structure and function as they impact on smooth muscle contractility.