Publications

Extracellular vesicles (EVs) are potent mediators in cell-cell communication that regulate diverse cell functions through the delivery of their bioactive cargo molecules to recipient cells. Previous work from our group demonstrated elevated plasma EV levels in patients and animals following septic or inflammatory insults, with a substantial proportion originating from neutrophils. As frontline defenders against bacterial infection, activated neutrophils release germicidal factors, some of which circulate systemically and inflict collateral tissue damage at a distance, including the brain. The role of neutrophil-derived EVs in regulating blood-brain barrier (BBB) structure and permeability after septic injury remains poorly defined. In this study, we first characterized EV production by mouse neutrophils stimulated with bacterial lipopolysaccharide (LPS) and subsequently investigated their functional and mechanistic effects on BBB integrity under in vivo and in vitro settings. Nanoparticle tracking analysis (NTA), immunoblotting, and transmission electron microscopy (TEM) revealed that LPS stimulation of neutrophils promoted EV secretion, indicated by increased particle number and protein content. Systemic administration of these EVs in mice induced cerebral microvascular leakage of plasma tracers (sodium fluorescein, at 376-Da; and dextran at 3-kDa) as quantified by near-infrared (NIR) nano-imaging and fluorometric assays. In cultured brain microvascular endothelial monolayers, EVs from naïve unstimulated neutrophils exerted minimal effects, whereas EVs from LPS-stimulated neutrophils caused a concentration-dependent reduction in transendothelial electrical resistance (TER) and a significant increase in solute permeability, indicative of paracellular hyperpermeability. Confocal microscopy revealed that tight junction proteins claudin-5 and zonula occludens-1 (ZO-1), which normally form continuous belt-like structures at endothelial cell–cell contacts, appeared discontinuous or fragmented upon EV internalization. Consistently, endothelial cells exposed to activated neutrophil-derived EVs exhibited reduced expression of tight junction proteins. Furthermore, TEM of brain capillaries from EV-injected mice provided ultrastructural evidence of tight junction disruption. Collectively, these findings suggest that neutrophil activation in response to infection promotes BBB leakage through the release of EVs capable of compromising endothelial tight junction integrity.

Laminin, by interacting with its receptors (mainly integrins and dystroglycan), exerts a variety of important functions in multiple organs. Loss-of-function studies have described the essential roles of laminin receptors in both physiological and pathologic conditions. This review summarizes the pathology and loss-of-function phenotypes of laminin receptors, including integrin-α3, integrin-α6, integrin-α7, integrin-β1, integrin-β4, and dystroglycan, focusing on the skin, kidney, skeletal muscle, peripheral nervous system, mammary gland, lung, and heart. To explore the functional redundancy/compensation among different laminin receptors, the phenotypes of compound knockout mice are compared with that of single mutants. Next, key signaling pathways downstream of each laminin receptor are summarized and compared. In addition, key questions in the field and future directions are also discussed. The aim of this review was to provide a synthetic review on loss-of-function studies of laminin receptors and foster the formation and testing of new hypotheses in the field.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent clinical challenge, particularly among aging and postmenopausal women. Emerging evidence highlights a significant role of adipose tissue, especially adipose tissue surrounding the heart, in the pathogenesis of HFpEF. Visceral fat depots function as endocrine and inflammatory organs. Coupled with hormonal changes during menopause, adipose tissue contributes to cellular senescence and myocardial dysfunction. This brief review summarizes the mechanistic links among adipose tissue, sex hormones, and depot-specific inflammation in HFpEF, and underscores potential targets for future research and therapeutic intervention. 

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by the deposition of amyloid-beta (Aβ) peptides within the walls of small- and medium-sized cerebral vessels, including arteries and capillaries but rarely veins. This vascular amyloid burden compromises vessel integrity, causes hemorrhages, and contributes to cognitive decline. Efficient Aβ clearance is critical for preventing its pathological accumulation. Thus, understanding the molecular players within the vascular microenvironment is essential. Laminin, a key glycoprotein of the vascular basal lamina (BL), is fundamental to maintaining structural stability of the vessels and regulating interactions among endothelial cells, pericytes, and the extracellular matrix. However, controversial findings exist on how laminin regulates Aβ aggregation and clearance, with both inhibitory and facilitative effects reported. Genetic variations in laminin subunits, their cell-specific expression pattern, and BL remodeling during CAA further complicate this relationship. This review synthesizes current knowledge on vascular Aβ deposition and elimination in CAA, with a particular focus on the critical roles of the BL/laminin and ApoE in shaping the perivascular microenvironment. First, we introduce Aβ processing relevant to CAA and the mechanisms of Aβ clearance in the CNS. Next, laminin-Aβ interactions and their functions in Aβ clearance are summarized. Thirdly, laminin changes and BL remodeling in CAA are discussed. Finally, we discuss the knowledge gap in the field and fundamental questions that need to be answered in future research. Defining the functions of the BL and ApoE within the pathological context of Aβ-rich vasculature may yield new insights into CAA pathogenesis and reveal therapeutic targets to limit vascular amyloid accumulation. Our goal is to provide a concise review on this matter in order to facilitate new hypotheses in the field. 

Pericytes, which share markers with smooth muscle cells (SMCs), are heterogenous cells. Pericytes in the brain and skeletal muscle have different embryonic origins, representing distinct subpopulations. One challenge in the field is that there are no subpopulation-specific pericyte markers. Here, we compared the transcriptomes of muscle pericytes and SMCs, and identified 741 muscle pericyte-enriched genes and 564 muscle SMC-enriched genes. Gene ontology analysis uncovered distinct biological processes and molecular functions in muscle pericytes and SMCs. Interestingly, the Venn diagram revealed only one gene shared by brain and muscle pericytes, suggesting that they are indeed distinct subpopulations with different transcriptional profiles. We further validated that GSN co-localized with PDGFRβ⁺SMA⁻ cells in small and large blood vessels but not PDGFRβ⁺SMA⁺ cells, indicating that GSN predominantly marks pericytes and fibroblasts rather than SMCs in skeletal muscle. Negligible levels of GSN were detected in the brain. These findings indicate that GSN may serve as a selective marker for muscle pericytes.