| dc.description.abstract |
<p>Angiogenesis, the production of new vessels from pre-existing vasculature, is a
complex biological process that is dependent on a series of regulated events, including
endothelial cell (EC) proliferation, migration, survival, and capillary morphogenesis
(tube formation). These events are required for angiogenesis to occur properly and
the steps are regulated by a variety of vascular growth factors and their receptors.
Tie2, an endothelial receptor tyrosine kinase (RTK), is required for embryonic and
postnatal angiogenesis. Studies have demonstrated that Tie2 is proteolytically cleaved,
producing a 75 kDa soluble receptor fragment (sTie2). However, the mechanisms and
function of sTie2 have not been elucidated. Here, we investigated signaling pathways
and effector molecule(s) responsible for Tie2 cleavage. Additionally, we investigated
the role of other growth factors and conditions on the degree of Tie2 cleavage. Finally,
we examined sTie2 levels in peripheral artery disease, a human model of ischemic disease.
We demonstrated that Tie2 cleavage is VEGF- and PI3K/Akt-dependent and sTie2 can bind
Ang1 and Ang2 and prevent ligand-mediated Tie2 activation and downstream cellular
responses. Also, ADAM15 cleaves Tie2 in a hypoxia-dependent manner and this response
was also observed to be VEGF-mediated. With respect to peripheral artery disease,
sTie2 levels were only significantly elevated in the most angiogenically compromised
group (critical limb ischemia) of patients. These data shed light on the mechanism
and function of Tie2 cleavage and suggest a role for sTie2 in mediating the angiogenic
process.</p>
|
|
