Date of Award

January 2015

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Michael Simons

Subject Area(s)

Physiology, Developmental biology, Cellular biology

Abstract

Syndecan2 is a member of the Syndecan family of transmembrane proteoglycans, expressed broadly in mammals. Syndecan2, along with Syndecan4, is expressed in the vasculature of mouse and man. Global deletion of Syndecan2 in mice does not affect viability and fertility of mice. However, it does result in defects in vascular smooth muscle cell coverage of the dermal vasculature of the mouse embryo.

We here report that lineage specific deletion of Syndecan2 in vascular smooth muscle results in delayed development of vascular smooth muscle coverage in the developing retinal vasculature. Postnatally, mice that lack Sdc2 in vascular smooth muscle mice exhibit gaps in smooth muscle coverage and reduced extent in coverage of retinal arterioles. Furthermore, smooth muscle cells have a disorganized and dysplastic appearance in the arterial wall in all tissues examined.

In the adult mouse, Syndecan2 deletion also results in hypotension in the systemic circuit without an accompanying decrease in vasopressor responsiveness. Pulmonary pressures in mice that lack Sdc2 in smooth muscle are equal to those of their wild-type littermates in normoxia. After exposure to chronic hypoxia however, mice lacking Syndecan2 in their smooth muscle are protected from the development of hypoxia-induced pulmonary arterial hypertension.

In vitro, vascular smooth muscle cells lacking Syndcan2 exhibit defects in expression of Notch3 and its downstream targets. They also exhibit numerous abnormalities in cytoskeletal dynamics. These defects may be rescued by re-expressing the intracellular domain of Syndecan2, are dependent on its PDZ-binding domain and likely are due to PDZ-dependent Sdc2-Syntenin1 complex formation.

Taken together, these findings assert that Sdc2 is a key regulator in the development and differentiation of vascular smooth muscle. Furthermore, it is a therapeutic target that might slow the progression of pulmonary arterial hypertension.  

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