Role of SRPK1 in peripheral ischemia

动脉粥样硬化导致缺血，刺激单核细胞外渗/分化为巨噬细胞，巨噬细胞分泌包括血管内皮生长因子在内的诱导侧支血管形成的因子。在外周血管疾病(PVD)患者中，这种胶原化受到损害，循环中的单核细胞表达抗血管生成剪接变异体VEGF-A165b。在PVD和肥胖的小鼠模型中，该变体表达上调。中和VEGF-A165b可使侧支血管再生，并在这些模型中恢复血流，提示预防VEGF-A165b的表达可能在治疗糖尿病PVD方面有用。我们现在有证据表明，通过刺激剪接因子蛋白磷酸化控制选择性剪接的富含丝氨酸的精氨酸(SR)蛋白，通过它们在单核细胞中的作用，是外周缺血侧支循环形成的关键调节因素。我们已经在小鼠身上证明，从药理上或通过单核细胞特异性敲除抑制剪接因子激酶SRPK1，可以防止受损的侧枝形成，并恢复单核细胞Wnt5a信号高激活的转基因动物的血液流动。我们现在打算确定a)这一机制是否对II型糖尿病有效。B)抑制或敲除单核细胞中的SRPK1导致促进侧枝生长的机制。

Atherosclerosis causes ischemia, stimulating extravasation/differentiation of monocytes into macro-phages, which secrete factors, including VEGF, that induce collateral vessel formation. This collat-eralisation is impaired in patients with peripheral vascular disease (PVD), where circulating mono-cytes express the anti-angiogenic splice variant, VEGF-A165b. In mouse models of PVD and obesity, this variant is upregulated. Neutralisation of VEGF-A165b allows regrowth of collaterals, and restores blood flow in these models, suggesting that prevention of VEGF-A165b expression could be therapeu-tically useful in diabetic PVD. We now have evidence that stimulation of splicing factor kinases that phosphorylate Serine-Arginine rich (SR) proteins controlling alternative splicing are critical regulators of collateral formation in peripheral ischemia, through their action in monocytes. We have shown in mice that inhibition of the splicing factor kinase SRPK1, pharmacologically, or by monocyte specific knockout, can prevent impaired collateral formation and restore blood flow in transgenic animals with hyperactivated monocyte Wnt5a signalling. We now intend to determine a) whether this mechanism is effective in type II diabetes. b) the mechanisms through which SRPK1 inhibition or knockout in monocytes result in enhanced collateral growth.