| dc.description.abstract |
<p>Maintenance of vascular homeostasis is an active process that is dependent on continuous
signaling by the quiescent endothelial cells (ECs) that line mature vessels. Defects
in vascular homeostasis contribute to numerous disorders of significant clinical impact
including hypertension and atherosclerosis. The signaling pathways that are active
in quiescent ECs are distinct from those that regulate angiogenesis but are comparatively
poorly understood. Here we demonstrate that the previously uncharacterized scaffolding
protein Caskin2 is a novel regulator of EC quiescence and that loss of Caskin2 in
mice results in elevated blood pressure at baseline. Caskin2 is highly expressed in
ECs from various vascular beds both in vitro and in vivo. When adenovirally expressed
in vitro, Caskin2 inhibits EC proliferation and migration but promotes survival during
hypoxia and nutrient deprivation. Likewise, loss of Caskin2 in vivo promotes increased
vascular branching and permeability in mouse and zebrafish models. Caskin2 knockout
mice are born in normal Mendelian ratios and appear grossly normal during early adulthood.
However, they have consistently elevated systolic and diastolic blood pressure at
baseline and significant context-dependent abnormalities in systemic metabolism (e.g.,
body weight, fat deposition, and glucose homeostasis). Although the precise molecular
mechanisms of these effects remain unclear, we have shown that Caskin2 interacts with
several proteins known to have important roles in endothelial biology and cardiovascular
disease including the serine/threonine phosphatase PP1, the endothelial receptor Tie1,
and eNOS, which is a critical regulator of vascular homeostasis. Ongoing work seeks
to further characterize the functions of Caskin2 and its mechanisms of action with
a focus on how Caskin2-mediated regulation of endothelial phenotype relates to its
systemic effects on cardiovascular and metabolic function.</p>
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