Coronary artery disease (CAD) occurs when blood vessels supplying the heart develop atherosclerotic plaques that limit blood flow. A suggested strategy for treating CAD, which if ignored can lead to a heart attack, is to promote the growth of new blood vessels to compensate for dysfunctional ones. To this end, researchers have identified factors controlling coronary blood vessel development, including the transcription factor Dach1. In mice lacking Dach1, embryonic coronary artery development is stunted. But, whether over-producing Dach1 boosts heart vessel development, and whether it would work in the adult were unanswered questions. To find out, Raftrey and colleagues engineered inducible gain-of-function Dach1 mice. After finding that Dach1 over-expression in the embryo did indeed boost cardiac artery development, the team induced Dach1 in adult mice for 6 weeks. While there were no apparent differences in artery growth between these animals and controls under normal conditions, after a myocardial infarction the animals over-expressing Dach1 had better recovery and survival with increased artery growth and heart function. The results pave the way for studying the mechanics of Dach1-mediated protection and how they might be leveraged as potential CAD treatments.

Aging is associated with declining tissue function and an assortment of health issues. But, in rodents at least, certain factors including the plasma of youthful animals and the exosomes of stem cells, can have rejuvenating effects on old animals. Exosomes are small membrane-bound particles containing cellular contents that circulate in the blood after their release from cells. Zhang and colleagues now show that, as rats age, the animals’ serum exosomes accumulate pro-inflammatory mediators such as C3a and C3b. Furthermore, when aged rats were subjected to a stroke and then injected with serum exosomes (twice a day for three days) isolated from either old or young rats, those receiving the youthful exosomes fared better, in terms of infarct size and sensorimotor deficits, while those receiving aged exosomes fared worse. The team went on to show that the injected exosomes accumulate at the site of stroke injury, but those from old donors caused more microglial phagoptosis of neurons with reduced synaptic function than those from young donors. Preventing C3a activity on microglia reversed the effects of the old exosomes and improved stroke outcome, the team showed, suggesting that such modulation of inflammatory molecules might be a treatment strategy for stroke.

Insulin resistance is a major hallmark of type 2 diabetes. But, recent studies in mice suggest resistance to insulin-like growth factor 1 (IGF1-) is also a feature of the disease. Indeed, mice genetically engineered to have muscle cells resistant to both insulin and IGF-1, develop a form of diabetes. And, as Viswambharan and colleagues now show, humans with diabetes and atherosclerosis also have insulin and IGF-1 resistant cells. The team also examined the particular effects of endothelial-specific insulin and IGF-1 resistance in mice and found that, unlike the previously studied animals whose muscle cells were resistant to the two hormones, mice with endothelial-specific resistance did not develop diabetes. Instead glucose uptake into the animals’ muscle and fat tissue was increased compared with that seen in control animals. The team went on to uncover the molecular mechanism of this unexpected favorable effect, showing that altered endothelial production of ROS—specifically increased hydrogen peroxide—primed the muscle and fat for glucose uptake. The results reveal a hitherto unexplored crosstalk between the endothelium and fat and muscle during metabolic stress that could potentially be exploited for novel diabetes treatments.

当为心脏供血的血管形成限制血流的动脉粥样硬化斑块时，就会发生冠状动脉疾病 (CAD)。治疗 CAD 的建议策略是促进新血管的生长以补偿功能失调的血管，如果忽视它会导致心脏病发作。为此，研究人员已经确定了控制冠状血管发育的因素，包括转录因子 Dach1。在缺乏 Dach1 的小鼠中，胚胎冠状动脉发育受阻。但是，过度产生的 Dach1 是否会促进心脏血管发育，以及它是否会在成人中发挥作用，这些都是悬而未决的问题。为了找到答案，Raftrey 及其同事设计了可诱导的功能获得性 Dach1 小鼠。在发现胚胎中 Dach1 的过度表达确实促进了心脏动脉发育后，该团队在成年小鼠中诱导 Dach1 6 周。虽然在正常条件下这些动物和对照之间的动脉生长没有明显差异，但在心肌梗塞后，过表达 Dach1 的动物具有更好的恢复和存活，动脉生长和心脏功能增加。结果为研究 Dach1 介导的保护机制以及如何将其用作潜在的 CAD 治疗铺平了道路。

衰老与组织功能下降和各种健康问题有关。但是，至少在啮齿类动物中，某些因素，包括年轻动物的血浆和干细胞的外泌体，可以对老年动物产生恢复活力的作用。外泌体是包含细胞内容物的膜结合小颗粒，从细胞中释放后会在血液中循环。Zhang 及其同事现在表明，随着大鼠年龄的增长，动物的血清外泌体会积累促炎介质，如 C3a 和 C3b。此外，当老年大鼠遭受中风，然后注射从老年或年轻大鼠中分离的血清外泌体（每天两次，持续三天）时，接受年轻外泌体的那些在梗死面积和感觉运动缺陷方面表现更好，而那些接受老化外泌体的人情况更糟。该团队继续表明，注射的外泌体在中风损伤部位积聚，但与年轻供体相比，来自老年供体的外泌体导致突触功能降低的神经元的小胶质细胞吞噬更多。研究小组表明，防止小胶质细胞上的 C3a 活性逆转了旧外泌体的影响并改善了中风结果，这表明炎症分子的这种调节可能是中风的一种治疗策略。

胰岛素抵抗是 2 型糖尿病的主要标志。但是，最近对小鼠的研究表明，对胰岛素样生长因子 1 (IGF1-) 的抵抗也是这种疾病的一个特征。事实上，经过基因工程改造后，肌肉细胞对胰岛素和 IGF-1 都具有抗性的小鼠会患上一种糖尿病。而且，正如 Viswambharan 及其同事现在所表明的，患有糖尿病和动脉粥样硬化的人也有胰岛素和 IGF-1 抗性细胞。该团队还研究了内皮特异性胰岛素和 IGF-1 抵抗对小鼠的特殊影响，发现与先前研究的肌肉细胞对这两种激素有抵抗力的动物不同，具有内皮特异性抵抗的小鼠不会患上糖尿病。相反，与对照组动物相比，动物肌肉和脂肪组织的葡萄糖摄取增加了。该团队继续揭示这种意想不到的有利效应的分子机制，表明内皮细胞产生的 ROS 改变——特别是增加过氧化氢——为肌肉和脂肪吸收葡萄糖提供了准备。结果揭示了代谢压力期间内皮与脂肪和肌肉之间迄今为止尚未探索的串扰，这可能被用于新的糖尿病治疗。