Role of SRPK1 in peripheral ischemia

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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.