Blanco-Colio, L. M. | bioRxiv Science

bioRxiv2025

Attenuation of endothelial glycocalyx shedding and endocan modulation by Sulodexide in murine models of anaphylaxis.

BackgroundAnaphylaxis is an acute life-threatening reaction. Research into the vascular endothelium and its components may improve disease management and patient outcomes. ObjectiveWe investigated the endothelial glycocalyx (eGCX) and its pathophysiological role in murine anaphylaxis, aiming to identify novel diagnostic and therapeutic targets. MethodsActive systemic anaphylaxis (ASA) and passive systemic anaphylaxis (IgE-PSA and IgG1-PSA) models were evaluated in mice. Sulodexide (Sdx) was administered as a prophylactic treatment. eGCX structure and N-acetylglucosamine residues in mouse aortic tissue were analyzed by electron microscopy and wheat germ agglutinin (WGA) staining. Endocan (ESM-1) levels in mouse aorta and plasma were determined by immunofluorescence and ELISA. Human sera from beta-lactam-induced anaphylaxis and endothelial cell (EC) secretome samples were also analyzed. ResultsASA, IgE-PSA, and IgG1-PSA models showed reduced eGCX surface area and thickness. N-acetylglucosamine and ESM-1 levels decreased in aortic tissue but increased in plasma, indicating glycocalyx shedding. Consistently, ESM-1 secretion was enhanced in ECs exposed to acute anaphylactic sera. ESM-1 and hyaluronic acid levels differed significantly between anaphylactic patients and non-allergic controls. Sdx reduced reaction severity in ASA and IgE-PSA, increased survival in ASA, and prevented eGCX disruption and ESM-1 release. ConclusionseGCX shedding, particularly of ESM-1, acts as a key mediator in murine anaphylaxis. Sdx prophylaxis protects against severe reactions and improves survival. Clinical ImplicationTherapies based on glycosaminoglycans and proteoglycans may mitigate anaphylaxis severity, and monitoring eGCX dynamics could aid diagnosis. Capsule summaryEndothelial glycocalyx shedding contributes to anaphylaxis pathophysiology; targeting its preservation and measuring HA and ESM1 may offer novel diagnostic and therapeutic strategies for clinicians.

immunology↗

bioRxiv2024

Integrated Stress Response Triggered by Excessive Glycosylation Drives Thoracic Aortic aneurysm

Thoracic aortic aneurysms and dissections (TAAD) are marked by degenerative changes in the aortic media. Marfan syndrome is the most common inherited connective tissue disorder associated with TAAD. While vascular smooth muscle cell (VSMC) metabolism is emerging as a targetable driver of aortic aneurysm, surgical interventions remain the primary strategy to prevent aortic dissection. Our research indicates that the hexosamine biosynthetic pathway (HBP), a branch of glycolysis, is upregulated in aortas from the Fbn1C1041G/+ Marfan Syndrome mouse model. Enhancing HBP activity promotes aortic dilation and accumulation glycan-rich extracellular matrix, contributing to aortic medial degeneration in wild-type mice. Mechanistically, fueling HBP activity induces VSMC dysfunction through excessive glycosylation, which activates the Integrated Stress Response (ISR). Pharmacological inhibition of HBP, along with ISR inhibition, successfully reverses aortic dilation and aortic medial degeneration in Fbn1C1041G/+ Marfan Syndrome mouse model. Additionally, Marfan Syndrome patients show elevated levels of HBP metabolites in blood plasma and serum, and heightened HBP-ISR signaling in patients with TAAD. These findings unveil a potential causative role for the HBP-ISR axis in medial degeneration in human TAAD, underscoring the need for evaluating HBP and ISR pathway as novel biomarkers and therapeutic strategies for thoracic aortic aneurysm.

molecular biology↗