Etulain Julia, Negrotto Soledad, Tribulatti María Virginia, Croci Diego Omar, Carabelli Julieta, Campetella Oscar, Rabinovich Gabriel Adrián, Schattner Mirta
Laboratory of Experimental Thrombosis, Institute of Experimental Medicine, CONICET-National Academy of Medicine, Buenos Aires, Argentina.
Institute of Biotechnological Investigations, Technologic Institute of Chascomús-National University of San Martín, CONICET, Buenos Aires, Argentina.
PLoS One. 2014 Apr 30;9(4):e96402. doi: 10.1371/journal.pone.0096402. eCollection 2014.
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.
血小板通过释放储存于其α-颗粒中的血管生成调节因子来促进血管形成。半乳糖凝集素是一类能结合β-半乳糖苷残基的凝集素家族，在炎症组织和癌组织中上调，触发血小板活化并介导血管生成过程。在此，我们旨在阐明血小板衍生的促血管生成分子的释放是否可能是半乳糖凝集素促进新生血管形成的另一种机制。我们发现半乳糖凝集素家族的不同成员可选择性调节人血小板血管生成分子的释放。半乳糖凝集素（Gal）-1、-3和-8可触发血管内皮生长因子（VEGF）释放，而只有Gal-8能诱导内皮抑素分泌。Gal-8诱导的VEGF释放被COX-1、蛋白激酶C（PKC）、p38和Src激酶抑制剂部分抑制，而Gal-1诱导的VEGF分泌被PKC和细胞外信号调节激酶（ERK）阻断所抑制，Gal-3通过PKC依赖性途径选择性触发VEGF释放。关于内皮抑素，在存在PKC、Src和ERK抑制剂的情况下，Gal-8未能刺激其释放，而阿司匹林或p38抑制剂对内皮抑素释放无影响。尽管有VEGF或内皮抑素分泌，但每种半乳糖凝集素刺激产生的血小板释放物在体外均可刺激血管生成反应，包括内皮细胞增殖和管状形成。血小板的血管生成活性独立于VEGF，归因于每种半乳糖凝集素独特释放的其他促血管生成分子的协同作用。因此，血小板衍生的血管生成分子的分泌可能是半乳糖凝集素促进血管生成反应的另一种机制，对其选择性阻断可能会导致开发与血管生成相关疾病的治疗策略。
