Targeting Endothelial Pathological Calcium Signaling Accelerates Resolution of SARS-CoV-2-Induced ARDS

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by diffuse alveolar damage, pulmonary edema, and severe hypoxemia, with limited therapeutic options. Increasing evidence identifies endothelial dysfunction and vascular barrier disruption as central drivers of ARDS pathogenesis, particularly in the context of SARS-CoV-2 infection. This thesis investigates the role of microtubule-associated End Binding Protein 3 (EB3) in regulating pathological calcium signaling and endothelial barrier integrity during acute lung injury. I hypothesized that EB3-mediated pathological calcium signaling promotes endothelial dysfunction and impairs vascular repair, and that pharmacological inhibition of EB3 can restore barrier function and accelerate lung regeneration. Using complementary murine models of SARS-CoV-2–induced ARDS, including MA10 infection and K18-hACE2 transgenic mice, I evaluated the therapeutic efficacy of a novel synthetic EB3 inhibitor termed Vascular Therapeutics-109. VT-109 treatment significantly reduced pulmonary vascular leakage, suppressed inflammatory signaling, and improved overall lung injury without affecting viral replication. Mechanistically, EB3 inhibition attenuated pathological calcium signaling and activated the transcription factor FOXM1, a key regulator of endothelial regeneration. VT-109 enhanced endothelial proliferation, restored inter-endothelial junction integrity, and promoted resolution of vascular injury. Notably, treatment also facilitated epithelial repair by accelerating alveolar type II to type I cell transdifferentiation, contributing to restoration of the alveolar-capillary barrier. Collectively, these findings identify EB3 as a critical upstream regulator of endothelial dysfunction in ARDS and establish its inhibition as a novel therapeutic strategy. Targeting pathological calcium signaling represents a promising approach to simultaneously suppress inflammation and promote vascular and epithelial regeneration in acute lung injury.

Author dc:creator

• Wan Ching Chan (24399749)

• Biology, Cell
• Biology, Molecular

Statement dc:rights

• In Copyright

DOI dc:identifier

https://doi.org/10.25417/uic.32994239.v1

OAI identifier oai:identifier

oai:figshare.com:article/32994239