Thrombospondin-1 is a large glycoprotein that is
synthesized and secreted by many cell types in response to injury and certain growth
factors. Thrombospondin-1 binds its receptor
CD36 and activates it. Activated
CD36 associates with Fyn and
stimulates its activity. Thrombospondin-1 signaling through
the CD36/ Fyn pathway leads to
activation of Mitogen-activated protein kinase p38 (p38MAPK)
via an unknown mechanism. p38MAPK activates by
phosphorylation Caspase-8, which in turn cleaves and
activates Caspase-3. Caspase-3
activation provides the cell with an apoptotic signal and therefore leads to inhibition
of angiogenesis , .
Thrombospondin -1 regulates
NO/ cGMP signaling acting
through both CD36 and CD47.
Thrombospondin-1 binding to
CD36 inhibits uptake of Myristic
acid . Myristic acid
stimulates Endothelial nitric oxide synthase (eNOS)
activity, augmenting NO production . NO in turn activates Soluble
guanylate cyclases, among them Guanylate cyclase 1, soluble.
Guanylate cyclases are enzymes catalyzing cGMP production.
cGMP is involved in regulation of proangiogenic responses.
cGMP also regulates smooth muscle contraction through a
Protein kinase, cGMP-dependent, type I (Protein kinase G1)/
Protein phosphatase 1, regulatory subunit 12A (MLCP (reg))/
Protein phosphatase 1, catalytic subunit, beta isoform (MLCP
(cat)) pathway. Thrombospondin-1 binding to
CD47 disrupts cGMP signaling,
apparently at the level of Guanylate cyclase 1, soluble.
Thus Thrombospondin-1 binding to
CD36 and CD47 leads to
inhibition of angiogenesis and vascular smooth muscle cell contraction , , .
In addition Thrombospondin-1 inhibits angiogenesis by
activation of Very low density lipoprotein receptor (VLDLR)
 and by inhibition of Fibroblast growth factor 2
(FGF2) and Vascular endothelial growth factor A
(VEGF-A) signaling, acting as a scavenger for the latter two
Thrombospondin-1 binds to and activates latent
Transforming growth factor, beta 1 (TGF-beta 1) . This interaction may play a role in TGF-beta 1
regulation of fibrosis development , , 
and wound healing .
Despite its generally inhibitory role in angiogenesis,
Thrombospondin-1 can exert proangiogenic activities under
specific conditions. Stimulation of angiogenesis by
Thrombospondin-1 occurs through its binding to
alpha-3/beta-1 integrin ,
alpha-4/beta-1 integrin  and
alpha-9/beta-1 integrin .
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