Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 Å cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho–ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease.

Significance: This paper analyzes the signaling network that regulates the size of artery lumens and thus their ability to transport blood to tissues. Lumen diameter is under close homeostatic regulation to match artery flow to the needs of downstream tissues. However, in atherosclerosis, this regulation is compromised, resulting in restricted blood flow and tissue ischemia. The elucidation of a Smad2/3 pathway that is specifically activated at low flow to trigger inward remodeling and thus restore normal shear stress levels not only reveals a mechanism of physiological regulation but also explains how activation of the same pathway by inflammatory factors in diseased arteries can lead to artery restriction.

The vascular system remodels throughout life to ensure adequate perfusion of tissues as they grow, regress, or change metabolic activity. Angiogenesis, the sprouting of new blood vessels to expand the capillary network, versus regression, in which endothelial cells die or migrate away to remove unneeded capillaries, controls capillary density. In addition, upstream arteries adjust their diameters to optimize blood flow to downstream vascular beds, which is controlled primarily by vascular endothelial cells sensing fluid shear stress (FSS) from blood flow. Changes in capillary density and small artery tone lead to changes in the resistance of the vascular bed, which leads to changes in flow through the arteries that feed these small vessels. The resultant decreases or increases in FSS through these vessels then stimulate their inward or outward remodeling, respectively. This review summarizes our knowledge of endothelial FSS–dependent vascular remodeling, offering insights into potential therapeutic interventions. We first provide a historical overview, then discuss the concept of set point and mechanisms of low-FSS–mediated and high-FSS–mediated inward and outward remodeling. We then cover in vivo animal models, molecular mechanisms, and clinical implications. Understanding the mechanisms underlying physiological endothelial FSS–mediated vascular remodeling and their failure due to mutations or chronic inflammatory and metabolic stresses may lead to new therapeutic strategies to prevent or treat vascular diseases.

Unmanned aerial vehicles (UAVs) are becoming more and more widely used in battlefield reconnaissance and target strikes because of their high cost-effectiveness, but task planning for large-scale UAV swarms is a problem that needs to be solved. To solve the high-risk problem caused by incomplete information for the combat area and the potential coordination between targets when a heterogeneous UAV swarm performs reconnaissance and strike missions, this paper proposes a distributed task-allocation algorithm. The method prioritizes tasks by evaluating the swarm’s capability superiority to tasks to reduce the search space, uses the time coordination mechanism and deterrent maneuver strategy to reduce the risk of reconnaissance missions, and uses the distributed negotiation mechanism to allocate reconnaissance tasks and coordinated strike tasks. The simulation results under the distributed framework verify the effectiveness of the distributed negotiation mechanism, and the comparative experiments under different strategies show that the time coordination mechanism and the deterrent maneuver strategy can effectively reduce the mission risk when the target is unknown. The comparison with the centralized global optimization algorithm verifies the efficiency and effectiveness of the proposed method when applied to large-scale UAV swarms. Since the distributed negotiation task-allocation architecture avoids dependence on the highly reliable network and the central node, it can further improve the reliability and scalability of the swarm, and make it applicable to more complex combat environments.

Significance: Inward remodeling of arteries to reduce lumen diameter is a major factor in disease progression and morbidity in multiple vascular diseases, including hypertension and atherosclerosis. However, molecular mechanisms controlling inward arterial remodeling remain largely undefined. In this study, we identify endothelial MEKK3 as an unexpected regulator of inward remodeling via inhibition of TGFβ-Smad2/3 signaling. Genetic deletion of MEKK3 in adult endothelium results in induction of TGFβ-Smad2/3 signaling, endothelial-to-mesenchymal transition, and inward remodeling in both pulmonary and arterial circuits. The latter process results in pulmonary and systemic hypertension and accelerates atherosclerosis. These results provide a basis for understanding the inward artery remodeling that leads to reduced blood flow to affected tissues and exacerbates hypertension in vascular disease.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Laminar shear stress from blood flow, sensed by vascular endothelial cells, protects from ASCVD by upregulating the transcription factors KLF2 and KLF4, which induces an anti-inflammatory program that promotes vascular resilience. Here we identify clustered γ-protocadherins as therapeutically targetable, potent KLF2 and KLF4 suppressors whose upregulation contributes to ASCVD. Mechanistic studies show that γ-protocadherin cleavage results in translocation of the conserved intracellular domain to the nucleus where it physically associates with and suppresses signaling by the Notch intracellular domain. γ-Protocadherins are elevated in human ASCVD endothelium; their genetic deletion or antibody blockade protects from ASCVD in mice without detectably compromising host defense against bacterial or viral infection. These results elucidate a fundamental mechanism of vascular inflammation and reveal a method to target the endothelium rather than the immune system as a protective strategy in ASCVD.