Abstract
Platelets contribute to vessel formation through the release of angiogenesis-modulating factors stored in their α-granules. Galectins, a family of lectins that bind β-galactoside residues, are up-regulated in inflammatory and cancerous tissues, trigger platelet activation and mediate vascularization processes. Here we aimed to elucidate whether the release of platelet-derived proangiogenic molecules could represent an alternative mechanism through which galectins promote neovascularization. We show that different members of the galectin family can selectively regulate the release of angiogenic molecules by human platelets. Whereas Galectin (Gal)-1, -3, and -8 triggered vascular endothelial growth factor (VEGF) release, only Gal-8 induced endostatin secretion. Release of VEGF induced by Gal-8 was partially prevented by COX-1, PKC, p38 and Src kinases inhibitors, whereas Gal-1-induced VEGF secretion was inhibited by PKC and ERK blockade, and Gal-3 triggered VEGF release selectively through a PKC-dependent pathway. Regarding endostatin, Gal-8 failed to stimulate its release in the presence of PKC, Src and ERK inhibitors, whereas aspirin or p38 inhibitor had no effect on endostatin release. Despite VEGF or endostatin secretion, platelet releasates generated by stimulation with each galectin stimulated angiogenic responses in vitro including endothelial cell proliferation and tubulogenesis. The platelet angiogenic activity was independent of VEGF and was attributed to the concerted action of other proangiogenic molecules distinctly released by each galectin. Thus, secretion of platelet-derived angiogenic molecules may represent an alternative mechanism by which galectins promote angiogenic responses and its selective blockade may lead to the development of therapeutic strategies for angiogenesis-related diseases.
Highlights
In the normal adult, angiogenesis, defined as the growth of new blood vessels from preexisting capillaries, is mostly limited to wound healing, pregnancy, and uterine cycling
As galectins can stimulate both neovascularization and platelet activation, we examined whether representative members of the three subfamilies of galectins including Gal-1 (‘proto-type’), Gal-3 (‘chimera-repeat’) or Gal-8 (‘tandem-repeat’) can trigger the release of platelet-derived molecules that promote or inhibit angiogenesis such as vascular endothelial growth factor (VEGF) or endostatin, respectively
Non-structurally related galectins such as Gal-1, -3 and -8 selectively modulated secretion of VEGF and endostatin from platelet a-granules, platelet activation induced by each galectin resulted in a VEGFindependent proangiogenic response, which was likely due to the combined action of several angiogenic mediators
Summary
Angiogenesis, defined as the growth of new blood vessels from preexisting capillaries, is mostly limited to wound healing, pregnancy, and uterine cycling. Emerging evidence implicates a key role for platelets in sitespecific neovascularization at ischemic tissues and the tumor microenvironment as they are major storage and delivery vehicles for pro- and antiangiogenic growth factors including vascular endothelial growth factor (VEGF), endostatin, and thrombospondin-1 (TSP-1), and cytokines and chemokines, such as stromalderived factor 1 a (SDF-1a) and IL-8 among others. These proteins are stored together with coagulation factors in platelet agranules, which upon activation can degranulate and influence the local angiogenic response [2,3]. Recent work from our laboratory has shown that both soluble and immobilized Gal-1 and Gal-8 bind and activate platelets, promoting adhesion, aggregation and granule secretion [19,20,21,22]
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