Department of Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Unit of Angiology, S. Giacomo Hospital, 31033 Castelfranco Veneto, Italy.
Int J Mol Sci. 2018 Dec 9;19(12):3954. doi: 10.3390/ijms19123954.
Sonic hedgehog (Shh) is a prototypical angiogenic agent with a crucial role in the regulation of angiogenesis. Experimental studies have shown that Shh is upregulated in response to ischemia. Also, Shh may be found on the surface of circulating microparticles (MPs) and MPs bearing Shh (Shh + MPs) have shown the ability to contribute to reparative neovascularization after ischemic injury in mice. The goal of this study was to test the hypothesis that, in humans with peripheral artery disease (PAD), there is increased number of circulating Shh + MPs. This was done by assessing the number of Shh + MPs in plasma of patients with PAD and control subjects without PAD. We found significantly higher number of Shh + MPs in plasma of subjects with PAD, compared to controls, while the global number of MPs-produced either by endothelial cells, platelets, leukocytes, and erythrocytes-was not different between PAD patients and controls. We also found a significant association between the number of Shh + MPs and the number of collateral vessels in the ischemic limbs of PAD patients. Interestingly, the concentration of Shh protein unbound to MPs-which was measured in MP-depleted plasma-was not different between subjects with PAD and the controls, indicating that, in the setting of PAD, the call for Shh recapitulation does not lead to secretion of protein into the blood but to binding of the protein to the membrane of MPs. These findings provide novel information on Shh signaling during ischemia in humans, with potentially important biological and clinical implications.
声波刺猬（Shh）是一种典型的血管生成剂，在调节血管生成中起着关键作用。实验研究表明，Shh 在缺血时上调。此外，Shh 可能存在于循环微颗粒（MPs）的表面，携带 Shh 的 MPs（Shh+MPs）已显示出在小鼠缺血损伤后有助于修复性新生血管形成的能力。本研究的目的是检验以下假说，即在患有外周动脉疾病（PAD）的人群中，循环的 Shh+MPs 数量增加。这是通过评估 PAD 患者和无 PAD 的对照受试者血浆中 Shh+MPs 的数量来完成的。与对照组相比，我们发现 PAD 患者血浆中 Shh+MPs 的数量明显更高，而内皮细胞、血小板、白细胞和红细胞产生的 MPs 的总数在 PAD 患者和对照组之间没有差异。我们还发现 Shh+MPs 的数量与 PAD 患者缺血肢体侧支血管的数量之间存在显著相关性。有趣的是，与 MPs 结合的 Shh 蛋白的浓度（在 MP 耗尽的血浆中测量）在 PAD 患者和对照组之间没有差异，这表明在 PAD 情况下，对 Shh 重编程的需求不会导致蛋白质分泌到血液中，而是导致蛋白质与 MPs 的膜结合。这些发现为人类缺血期间的 Shh 信号提供了新的信息，具有潜在的重要生物学和临床意义。
