Development of a Glycocalyx Mimetic to Treat Endothelial Cell Dysfunction

James R Wodicka, Purdue University

Abstract

Endothelial cell (EC) dysfunction is associated with many cardiovascular disease states including atherosclerosis, thrombosis, diabetes and sepsis. Dysfunctional ECs exhibit a compromised ability to vasodilate and have elevated levels of reactive oxygen species. Loss of the glycocalyx, a thin glycosaminoglycan-rich layer on the EC surface, is also a key feature of EC dysfunction and increases exposure of adhesion molecules such as E- and P-selectin and intercellular adhesion molecule-1 (ICAM-1), which initiate binding of platelets and leukocytes to the EC surface. Once bound, platelets and leukocytes can cause thrombosis and an increased inflammatory response, exasperating cardiovascular diseases. Current treatments for EC dysfunction remain limited. Therefore, a glycocalyx mimetic (termed EC-SEAL) consisting of a dermatan sulfate backbone and multiple adhesion molecule-binding peptides designed to bind to inflamed endothelium and prevent platelet/leukocyte binding was developed in order to create a more quiescent endothelial state. Multiple EC-SEAL variants have been evaluated and the lead variant was found to preferentially bind to E- and P-selectin as well as adhesion molecule-expressing ECs. Further, EC-SEAL inhibited platelet binding and activation in a dose-dependent manner and reduced thrombus formation in vivo in a murine model of deep vein thrombosis. EC-SEAL was also shown to reduce leukocyte interactions on both E- and P-selectin substrates, as well as inflamed ECs, under physiologically relevant shear stress. These findings indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction.

Degree

Ph.D.

Advisors

Goergen, Purdue University.

Subject Area

Biomedical engineering

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