Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA,
Angiogenesis. 2013 Oct;16(4):985-92. doi: 10.1007/s10456-013-9374-5. Epub 2013 Aug 4.
Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.
缺血性神经元组织中血管的再生对于减少疾病引起的组织损伤至关重要。在增殖性视网膜病变中，最初的血管损失导致视网膜缺血，这可能导致血管重新生长以恢复正常代谢并最大限度地减少损伤，或者进展为缺氧诱导的危及视力的病理性血管增生。目前尚不清楚视网膜神经元如何介导血管生长的再生以应对缺血性损伤。在这项研究中，我们旨在研究 Sirtuin 1（Sirt1），一种代谢调节蛋白去乙酰化酶，在介导缺血性神经元对氧诱导的缺血性视网膜病变（OIR）模型中血管再生长的反应中的潜在作用。我们发现 Sirt1 在 OIR 中的无血管缺血性视网膜中高度诱导。神经元 Sirt1 的条件性缺失导致血管向无血管区的再生显著减少，并增加缺氧诱导的病理性血管生长。这种效应可能独立于 PGC-1α，因为在敲除小鼠中缺乏 PGC-1α并不影响视网膜病变中的血管生长。我们发现，神经元 Sirt1 通过调节缺氧诱导因子 1α和 2α的去乙酰化和稳定性来控制血管再生，从而调节血管生成因子的表达。这些结果表明，缺血性神经元诱导 Sirt1 促进缺血性神经元区域的血管再生成，提示神经元 Sirt1 在介导缺血条件下的血管再生中具有新的作用，其潜在意义超出了视网膜病变。
