As well as being thoroughfares for immune cells, lymph vessels are drainage channels that help maintain tissue fluid homeostasis. This network of branching tubes grows as fluids begin to flow in the developing embryo. Indeed, fluid flow induces calcium influx into lymphatic endothelial cells (LECs), which in turn promotes proliferation and migration of the cells and, ultimately, sprouting of lymph tubules. But how do LECs detect fluid flow in the first place? Piezo1 is a flow-sensing mechanosensory protein known for its role in blood vessel development and, furthermore, certain mutations to Piezo1 cause abnormal lymphatic growth in humans. Choi and colleagues now show that Piezo1 is expressed in embryonic mouse LECs and that suppression of Piezo1 inhibits both flow-activated calcium entry (via the channel Orai1) and downstream target gene activation. Overexpression of Piezo1, by contrast, induced the target genes. The team went on to show that mice lacking either Piezo1 or Orai1 had lymphatic sprouting defects, and that pharmacological activation of Piezo1 in mice enhanced lymphangiogenesis and prevented edema after tail surgery. Together the results confirm Piezo1’s role in flow-dependent lymphatic growth and suggest it might be a target for treating lymphedema.

While overactivation of β1 and β2 adrenergic receptors can lead to heart damage, the same is not true for the third subtype—ADRB3. Activation of this receptor, which is primarily expressed in brown adipose tissue (BAT), is linked to beneficial metabolic activity and heart protection. And, as Lin and colleagues now show, this is not the only way ADRB3 protects the heart. The team studied mice with a BAT-specific deletion of ADRB3 and found, after a month of angiotensin II (Ang II)-induced hypertension, that the animals fared worse than controls (suffering exacerbated cardiac hypertrophy and fibrosis). In vitro experiments indicated this negative fibrotic effect of ADRB3 deletion was due, at least in part, to direct communication between the adipocytes and heart cells, specifically via adipocyte-released exosomes containing induced nitric oxide synthase (iNOS)—an enzyme previously implicated in cardiac dysfunction. The authors surmised that ADRB3 normally suppresses iNOS to protect the heart and showed that while exosomes with high iNOS exacerbated Ang-II-induced heart damage when infused into mice, silencing iNOS prevented this. The work thus highlights a novel BAT-to-heart communication system and identifies factors involved that could be clinically targeted to tackle heart disease.

Excessive plasma cholesterol together with systemic inflammation are contributing factors in atherosclerosis. While traditional remedies have been aimed at lowering a patient’s lipid levels, drugs that tackle inflammation are now also under investigation, including those that suppress interleukin-6 (IL-6)—an inflammatory cytokine implicated in the disease. Focusing on carotid artery disease—the presence of atherosclerotic plaques in major blood vessels supplying the brain—Kamtchum-Tatuene and colleagues investigated whether IL-6 levels correlated with disease severity. They examined levels of the cytokine and data from carotid artery ultrasounds—taken five years apart to assess the presence, severity and progression of plaques—for 4334 individuals enrolled in the Cardiovascular Health Study (CHS) cohort—an NIH-funded prospective population study. IL-6 was found to robustly correlate with and predict plaque severity independent of other cardiovascular risk factors. The study also determined a threshold IL-6 blood plasma level of 2.0pg/ml that identifies individuals with the highest likelihood of plaque vulnerability and progression. This threshold value, say the authors, could be used to select patients who might benefit from novel IL-6-lowering medications.

除了作为免疫细胞的通道外，淋巴管还是有助于维持组织液稳态的引流通道。当流体开始在发育中的胚胎中流动时，这种分支管网络就会增长。事实上，流体流动会诱导钙流入淋巴管内皮细胞 (LEC)，进而促进细胞的增殖和迁移，并最终促进淋巴管的萌发。但是，LEC 首先是如何检测流体流动的呢？Piezo1 是一种流量感应机械感觉蛋白，以其在血管发育中的作用而闻名，此外，Piezo1 的某些突变会导致人类淋巴管异常生长。Choi 及其同事现在表明，Piezo1 在胚胎小鼠 LEC 中表达，抑制 Piezo1 会抑制流动激活的钙进入（通过通道 Orai1）和下游靶基因激活。相比之下，Piezo1 的过表达诱导了靶基因。该团队继续表明，缺乏 Piezo1 或 Orai1 的小鼠存在淋巴发芽缺陷，并且在小鼠体内 Piezo1 的药理学激活增强了淋巴管生成并预防了尾部手术后的水肿。这些结果共同证实了 Piezo1 在依赖流动的淋巴生长中的作用，并表明它可能是治疗淋巴水肿的目标。Piezo1 在小鼠体内的药理学激活增强了淋巴管生成并预防了尾部手术后的水肿。这些结果共同证实了 Piezo1 在依赖流动的淋巴生长中的作用，并表明它可能是治疗淋巴水肿的目标。Piezo1 在小鼠体内的药理学激活增强了淋巴管生成并预防了尾部手术后的水肿。这些结果共同证实了 Piezo1 在依赖流动的淋巴生长中的作用，并表明它可能是治疗淋巴水肿的目标。

虽然 β1 和 β2 肾上腺素能受体的过度激活会导致心脏损伤，但第三种亚型 ADRB3 的情况并非如此。这种主要在棕色脂肪组织 (BAT) 中表达的受体的激活与有益的代谢活动和心脏保护有关。而且，正如 Lin 及其同事现在所表明的，这并不是 ADRB3 保护心脏的唯一方法。研究小组研究了 BAT 特异性缺失 ADRB3 的小鼠，发现在一个月的血管紧张素 II (Ang II) 诱发的高血压后，这些动物的表现比对照组差（心脏肥大和纤维化加剧）。体外实验表明 ADRB3 缺失的这种负纤维化作用至少部分是由于脂肪细胞和心脏细胞之间的直接通讯，特别是通过脂肪细胞释放的含有诱导一氧化氮合酶 (iNOS) 的外泌体——一种先前与心脏功能障碍有关的酶。作者推测 ADRB3 通常会抑制 iNOS 以保护心脏，并表明，当注入小鼠体内时，虽然具有高 iNOS 的外泌体会加剧 Ang-II 诱导的心脏损伤，但沉默 iNOS 可以防止这种情况发生。因此，这项工作突出了一种新的 BAT 到心脏的通信系统，并确定了可能在临床上针对治疗心脏病的相关因素。

过量的血浆胆固醇和全身炎症是动脉粥样硬化的促成因素。虽然传统疗法旨在降低患者的血脂水平，但目前也在研究治疗炎症的药物，包括抑制白细胞介素 6 (IL-6)（一种与疾病有关的炎性细胞因子）的药物。专注于颈动脉疾病——供应大脑的主要血管中存在动脉粥样硬化斑块——Kamtchum-Tatuene 及其同事研究了 IL-6 水平是否与疾病严重程度相关。他们检查了 4334 名参加心血管健康研究 (CHS) 队列的人的细胞因子水平和颈动脉超声数据（相隔 5 年评估斑块的存在、严重程度和进展）——这是一项由 NIH 资助的前瞻性人群研究。发现 IL-6 与斑块严重程度密切相关并预测斑块严重程度，而与其他心血管危险因素无关。该研究还确定了 2.0pg/ml 的阈值 IL-6 血浆水平，可识别出斑块易损性和进展可能性最高的个体。作者说，这个阈值可用于选择可能受益于新型降低 IL-6 药物的患者。