During the development and shaping of the mammalian vascular system there is both growth of new vessels (angiogenesis) as well as pruning of unwanted ones. But while much is known about the molecular mechanisms of angiogenesis, relatively little is understood about pruning. Ehling and colleagues have now discovered that suppression of the phosphatase subunit B55α is a key feature of the pruning process. They showed that in mouse embryos, when vascular development is in full swing, B55α is widely expressed, but that in adult mice the enzyme’s expression is limited to sites of active angiogenesis, such as in tumors. Furthermore, genetic deletion of B55α in mice caused death in mid-to-late stages of embryogenesis as a result of vascular problems—the animals’ skin showed evidence of excessive vessel pruning—while switching off B55α in adult mice, when vascular development is largely complete, did not cause apparent problems. Such later stage inhibition of B55α could, however, significantly delay the growth of induced tumors, resulting in less dense tumor vasculature and reduced metastatic potential. Thus, say the authors, ramping up blood vessel pruning via inhibition of B55α could be a novel strategy for limiting tumor growth.

Brain arteriovenous malformations (bAVMs) are tangles of blood vessels, normally present from birth, in which the arteries are directly connected to the veins. As well as inducing headaches and seizures they are the leading cause of hemorrhagic stroke in children and young adults—the direct arterial pressure causing distention and eventual leaking of the adjoining veins. Vessel tissue recovered at the time of surgical resection of such malformations has been shown to contain somatic gain-of-function mutations in RAS GTPase (encoded by the gene KRAS), but whether such mutations directly cause bAVM had not been established. Fish and colleagues now provide this confirmation, showing that endothelial expression of constitutively active mutant KRAS in mice and zebrafish causes vascular malfomations and cranial hemorrhages. And, that inhibition of MEK kinase—a downstream mediator of RAS signaling—prevented hemorrhages in the mutant KRAS-carrying fish. In vitro studies also showed that overactive RAS GTPase caused excessive angiogenic behavior of endothelial cells. Together the work confirms the link between KRAS mutations and bAVMs, establishes animals models in which to further study the condition and suggests MEK inhibition as a potential strategy for non-surgical treatment.

Metabolic syndrome (MetS)—characterized by symptoms such as abdominal obesity, insulin resistance and elevated blood pressure—puts a person at greater risk of developing atherosclerosis. Perdomo and colleagues argue that this increased risk could in part be due to the type and abundance of extracellular vesicles (EVs) circulating in such patients’ blood. Indeed, EVs from MetS patients have been linked to endothelial dysfunction and inflammation—two factors contributing to atherosclerosis. And now the team has discovered that such MetS patient-derived EVs, which they show express higher than usual levels of the small GTPase Rap1, accumulate in both human and mouse atherosclerotic plaques. In mice, the accumulation correlated with plaque progression. The team also showed in vitro that patient-derived Rap1-positive EVs, but not those from healthy controls, promoted plaque-forming processes including endothelial cell permeabilisation, smooth muscle cell proliferation and migration, and expression of inflammatory cytokines. And, that inhibition of Rap1 prevented these EV-induced effects. The results suggest that Rap1-positive EVs could serve as both biomarkers of atherosclerosis in MetS patients and targets for therapies designed to slow the disease.

在哺乳动物血管系统的发育和成形过程中，既有新血管的生长（血管生成）也有多余血管的修剪。但是尽管对血管生成的分子机制了解很多，但对修剪的了解却很少。Ehling及其同事现已发现，抑制磷酸酶亚基B55α是修剪过程的关键特征。他们表明，在小鼠胚胎中，当血管发育如火如荼时，B55α被广泛表达，但是在成年小鼠中，该酶的表达仅限于活动性血管生成的部位，例如在肿瘤中。此外，由于血管问题（动物的皮肤显示出过度修剪血管的迹象），老鼠体内B55α的基因缺失导致了胚胎发生的中晚期死亡，而成年老鼠则关闭了B55α，当血管发育基本完成时，没有引起明显的问题。然而，对B55α的这种后期抑制可显着延迟诱导的肿瘤的生长，从而导致肿瘤脉管系统密度降低和转移潜能降低。因此，作者说，通过抑制B55α来增加血管修剪可能是限制肿瘤生长的一种新策略。

脑动静脉畸形（bAVM）是正常情况下从出生就存在的血管缠结，其中动脉直接与静脉相连。它们不仅引起头痛和癫痫发作，而且还是儿童和年轻人出血性中风的主要原因-直接动脉压导致扩张，并最终导致相邻静脉渗漏。已显示在外科切除此类畸形时恢复的血管组织在RAS GTPase中包含体细胞功能获得性突变（由基因KRAS编码），但尚未确定此类突变是否直接导致bAVM。Fish及其同事现在提供了这一证实，表明组成型活性突变体KRAS的内皮表达在小鼠和斑马鱼中引起血管畸形和颅内出血。而且，对MEK激酶（RAS信号的下游介质）的抑制可防止携带KRAS突变的鱼的出血。体外研究还表明，过度活跃的RAS GTPase会引起内皮细胞过度的血管生成行为。这项工作共同证实了KRAS突变与bAVM之间的联系，建立了动物模型以进一步研究病情并建议MEK抑制作为非手术治疗的潜在策略。

代谢综合征（MetS）以腹部肥胖，胰岛素抵抗和血压升高等症状为特征，使人患动脉粥样硬化的风险更高。Perdomo及其同事认为，这种增加的风险可能部分归因于此类患者血液中循环的细胞外囊泡（EV）的类型和数量。确实，来自MetS患者的EV与内皮功能障碍和炎症有关，这是导致动脉粥样硬化的两个因素。现在，研究小组发现，这种MetS患者来源的EV在人和小鼠的动脉粥样硬化斑块中均会积累较高水平的小GTPase Rap1。在小鼠中，积累与斑块进展相关。研究小组还在体外展示了患者来源的Rap1阳性电动汽车，但不是健康对照组的人，却促进了噬菌斑形成过程，包括内皮细胞通透性，平滑肌细胞增殖和迁移以及炎性细胞因子的表达。并且，Rap1的抑制阻止了这些EV诱导的作用。结果表明，Rap1阳性电动汽车既可作为MetS患者动脉粥样硬化的生物标志物，又可作为减慢疾病速度的疗法的靶标。