Bauer Sumpio, MD, PhD, FACS

The Vascular Surgery Research Laboratories are conducting studies on the role of hemodynamic forces in influencing the biology of the vascular wall. Dr. Bauer Sumpio and his team are specifically interested in the role of strain and pressure in modulating endothelial cell and smooth cell growth, morphology and production of vasoactive molecules and mitogens.

They are currently focused on the signal transduction pathways which couple the external force stimuli and the cytoplasmic and nuclear responses.

Dr. Sumpio have developed and characterized an instrument for exerting repetitive tensional deformation on cells in culture. Cells are grown on special culture plates with bottoms made of flexible silastic but coated with a hydrophilic surface. The culture dishes are placed over vacuum portsand the membrane bottoms are deformed to a given strain by the application of a vacuum. The vacuum is regulated by solenoid valves which are controlled by a computer program. Thus, Dr. Sumpio has managed to subject cells to different force regimens by varying the amplitude, frequency and duration of a deformation. Using this apparatus, he has shown that the phenotypic expression of both endothelial cells and smooth cells are altered with cyclic strain compared to the stationary state. Cell growth, morphology, production of growth factors and inhibitors, substances involved in coagulation, blood vessel vasamotor tone and extra-cellular-matrix elements are altered.

However, very little is known about the mechanism of transduction of the mechanical signals that induce gene transcription in responsive cells. The major impetus in this field has been to define the mechanosensor(s)' on the cells that are sensitive to the different external forces, the coupling intracellular pathways and the subsequentnuclear events which precede the cell response.

Recent work in Dr. Sumpio's laboratory has demonstrated the involvement of the phosphoinositol/protein kinase C and cAMP/protein kinase A pathways, activation of the fos and jun family of oncogenes and the involvement of the transcription factors AP-1, NF-kB and CRE with the initiation of cyclic strain or with an acute change cyclic strain frequency. They are currently attempting to determine the events which occur subsequently in the cell nucleus to induce transcriptional initiation.

Dr. Sumpio and and his team's underlying hypothesis is that the molecular basis of cellular events which occur in response to mechanical forces depends upon the establishment of specific patterns of gene expression achieved through a network both ubiquitous and tissue specific transcriptional regulatory proteins. They plan to define the necessary and sufficient promoter sequences involved in the regulation of gene transcription in cultured endothelial cells exposed to cyclic strain.

The upstream promoter for the human tPA gene is used as a model for these experiments. The group speculates that there are cyclic strain responsive promoter elements (CSRE). Whether the CSRE are similar to those activated with chemical agonists or whether there are ''novel'' elements remain to be determined.