Microvascular research最新文献

Alzheimer's disease (AD) and atherosclerosis (AS) are traditionally viewed as distinct neurodegenerative and vascular disorder respectively. However, emerging evidence reveals a profound molecular cross-talk and pathophysiological interplay between these two conditions. This review explores the molecular crossroads where AD and AS converge, identifying shared signaling pathways that offer novel therapeutic opportunities. At the center of this connection is amyloid-beta (Aβ), which serves as a systemic molecular nexus. While central Aβ accumulation is a hallmark of AD, peripheral Aβ, produced in tissues such as skeletal muscle and pancreas, can cross the blood-brain barrier (BBB) to induce endothelial dysfunction and neurovascular inflammation. This review highlights how common molecular hubs, including the PI3K/AKT/GSK3β, mTOR, PP2A, and PTEN signaling pathways, drive the pathogenesis of both diseases by regulating oxidative stress, inflammation, and autophagy. By addressing these shared mechanisms, the review proposes a paradigm shift toward dual-purpose therapies. Modulating Aβ clearance, inhibiting the over-activated GSK3β, or utilizing mTOR inhibitors and PP2A activators could concurrently mitigate neurodegeneration and stabilize atherosclerotic plaques. Ultimately, recognizing AD and AS as interconnected systemic disorders provides a compelling rationale for multidisciplinary clinical strategies and integrated pharmacological interventions to improve outcomes in an aging population.

Background: Resistant arterial hypertension (RAH) is defined as failure to achieve adequate blood pressure control despite the use of at least three antihypertensive drug classes at maximally tolerated doses, including a diuretic. This phenotype confers markedly elevated cardiovascular risk. Systemic microvascular dysfunction is believed to contribute significantly to its pathophysiology. In non-resistant arterial hypertension (NRAH), early endothelial impairment and increased vasomotor tone are present but may remain partially reversible. However, direct comparisons of microvascular function across RAH, NRAH, and normotensive individuals are limited.

Objective: To compare systemic microvascular function among patients with RAH, patients with NRAH, and normotensive controls using laser speckle contrast imaging.

Methods: Microvascular reactivity was assessed at baseline and during acetylcholine (ACh) and sodium nitroprusside (SNP) iontophoresis, as well as post-occlusive reactive hyperemia (PORH). Baseline microvascular conductance, areas under the curve (AUCs) for ACh and SNP, and PORH peak and delta responses were compared using one-way ANOVA.

Results: Baseline microvascular conductance was significantly higher in controls than in both hypertensive groups. Endothelium-dependent vasodilation (ACh AUC) showed progressive impairment from controls to NRAH to RAH. PORH responses demonstrated reduced peak microvascular conductance and smaller delta values in RAH compared with NRAH and controls. Endothelium-independent vasodilation (SNP AUC) was also diminished in RAH, suggesting structural arteriolar disorder.

Conclusion: RAH is associated with marked systemic microvascular impairment affecting both endothelial function and microvascular structure. These alterations occur alongside adverse metabolic and renal disorders, underscoring the complex interplay of vascular, metabolic, and renal mechanisms in treatment-resistant hypertension.

Tumour angiogenesis, a hallmark of cancer progression, involves the formation of new vasculature to sustain malignant growth. It is driven by complex molecular signalling networks responsive to hypoxia, inflammation, and metabolic stress. This article is an attempt to analyse and integrate recent insights into the molecular mechanisms underlying angiogenesis, its diagnostic and therapeutic implications, and its emerging intersection with ferroptosis - an iron-dependent, regulated form of cell death. Key pathways such as VEGF, PDGF, IGF, TGF-β and their downstream effectors such as PI3K/Akt, MAPK, ERK, etc., as well as molecular regulators linking oxidative stress and lipid peroxidation to angiogenic responses, are crucial in framing the tumour microenvironment. Understanding these pathways provides a foundation for developing novel combinatorial strategies targeting both angiogenesis and ferroptosis for improved cancer therapy.

Objective: Endothelial cells (ECs) are key structural and functional components of the blood-brain barrier (BBB). Mouse models are frequently used to study EC biology within the BBB, yet the extent to which human and mouse BBB ECs share conserved transcriptomic features remains unclear. Here, we systematically compare transcriptomic profiles of BBB capillary ECs from adult mice and humans.

Methods: We analyzed single-cell and single-nucleus RNA-sequencing datasets from adult mouse and human BBB capillary ECs. Candidate species-specific genes were further validated using two whole brain vasculature datasets, along with data from Allen Brain Atlas and Human Protein Atlas.

Results: Despite substantial overall conservation between species, 169 genes were consistently enriched in human BBB capillary ECs compared to mouse, whereas 386 genes were enriched in mouse BBB capillary ECs compared to human. Several genes, including A2M, RUNDC3B, BTNL9 and SPOCK3 exhibited predominant expression in human BBB capillary ECs, with minimal or undetected expression in mouse. Conversely, Tspan13, Pglyrp1, Ucp2 and Slco1c1 were specifically expressed in mouse BBB capillary ECs compared with human. Notably, a considerable proportion of differentially expressed genes belonged to the solute carrier (SLC) transporter family.

Conclusions: Our cross-species in-depth analysis reveals both broad conservation and distinct transcriptomic differences between human and mouse BBB capillary ECs. Together, our findings provide a valuable framework for interpreting mouse BBB data in a translational context and for guiding future studies of endothelial biology in the human brain.

Lipid homeostasis and vascular endothelial function are fundamental to cardiovascular health. This review systematically outlines the regulatory mechanisms that maintain the dynamic balance between the endothelium and systemic lipid metabolism, emphasizing the endothelium as an active regulator. The endothelium influences lipid metabolism in multiple organs by regulating vascular tone, angiogenesis, barrier integrity, and inflammatory response. Studies have demonstrated that genetic ablation of endothelial-specific genes disrupts lipid metabolism in key metabolic organs, including the liver, adipose tissue, and skeletal muscle. This impairment of endothelial function may result in obesity, insulin resistance, hyperlipidemia, and MASLD/MASH. The specific mechanisms linking endothelial dysfunction to systemic lipid metabolism are highlighted. This review clarifies the progression of systemic lipid metabolism disorders driven by an imbalance in the "endothelial-lipid metabolism homeostasis axis". Potential therapeutic strategies targeting this axis for lipid-metabolism disorders and related cardiovascular diseases are also discussed.

Objective(s): Diabetic retinopathy (DR), a severe microvascular complication of diabetes mellitus (DM), is recognized worldwide as the leading cause of visual impairment and blindness. FGL2 has been linked to microvascular endothelial cell injury and oxidative stress. This research aims to evaluate the role of FGL2 in influencing retinal microvascular endothelial cell injury and oxidative stress.

Materials and methods: Our study established a streptozotocin (STZ, 65 mg/kg)-induced diabetic rat model and cultured human retinal microvascular endothelial cells (HRMECs) under high glucose (HG, 30 mM) conditions. H&E staining and Evans blue leakage assay were performed to evaluate the pathological change and the vascular leakage in DR rats. Subsequently, we assessed the influence of FGL2 knockdown on endothelial barrier function, oxidative stress and the AKT/FOXO1/PLVAP pathway in vitro.

Results: FGL2 expression was upregulated in the retinal tissues of DR rats and HG-stimulated HRMECs. In HG-induced HRMEC monolayers, FGL2 knockdown inhibited FITC-dextran flux and increased transendothelial electrical resistance (TEER). Results of immunofluorescence staining of tight junction proteins reveal a decreased number of tight junction discontinuities in FGL2 knockdown-treated HRMEC cells compared to HG-treated HRMEC cells. Silencing of FGL2 decreased ROS production and MDA content, and elevated SOD and CAT activity in HG-treated HRMECs. Mechanistically, FGL2 silencing enhanced the phosphorylation of AKT^Ser473 and FOXO1^Ser256. Notably, dual-luciferase reporter assay and ChIP-qPCR were conducted to confirm the occupancy of FOXO1 at the PLVAP promoter. Crucially, the protective effects of FGL2 knockdown on barrier function and oxidative stress were effectively reversed by PLVAP overexpression.

Conclusion: Collectively, our research indicates that FGL2 knockdown can alleviate the impaired barrier function and oxidative stress in retinal microvascular endothelial cells induced by HG, through the AKT-FOXO1-PLVAP pathway.