Storage Stability
Endorepellin is the C-terminal domain V of the large heparan sulfate proteoglycan perlecan (HSPG2). It is released from the basement membrane by BMP-1/tolloid metalloproteinases and acts as a potent anti-angiogenic agent by engaging integrin alpha2beta1 on endothelial cells and triggering a VEGFR2 transactivation cascade that ultimately leads to cytoskeletal disruption and angiostasis.
Mechanism of Action
- Binds integrin alpha2beta1 on endothelial cells with high affinity via LG1-LG2 laminin G-like modules
- Integrin alpha2beta1 engagement triggers a signaling cascade: activation of SHP-1 phosphatase, VEGFR2 dephosphorylation and downregulation
- Loss of VEGFR2 signaling disrupts lamellipodia formation, reducing endothelial migration toward VEGF gradients
- Triggers alpha-actin reorganization and focal adhesion disassembly via FAK dephosphorylation
- Endorepellin LG3 subdomain retains bioactivity and is being explored as minimal anti-angiogenic unit
Research Findings
- Endorepellin identified by Io Jarvelainen and Renato Iozzo labs as perlecan-derived angiogenesis inhibitor
- Systemic endorepellin suppressed orthotopic breast and squamous cell carcinoma tumor growth in mice via angiogenesis inhibition
- Endorepellin expression reduced in tumor vasculature vs normal vessels, suggesting tumors escape suppression by downregulating perlecan processing
- LG3 minimal domain (aa4196-4391) retains anti-angiogenic activity and is more tractable for recombinant production
- Endorepellin induces autophagy in endothelial cells via PEX19/Beclin1 axis; distinct from apoptotic cell death
Research Protocols
- Recombinant endorepellin: 10-300 nM in endothelial tube formation and migration (Boyden chamber) assays
- In vivo mouse tumor models: 2-10 mg/kg IV every other day of recombinant endorepellin
- LG3 minimal fragment: 50-500 nM in cell-based anti-angiogenic screens
- Matrigel plug assay: 100-500 ng/plug to measure in vivo anti-angiogenic potency vs control
Interactions
- Integrin alpha2beta1 antagonists: block endorepellin binding and anti-angiogenic effect
- VEGF-A: endorepellin opposes VEGF-driven endothelial migration and tube formation
- Endostatin and tumstatin: complementary basement membrane-derived anti-angiogenic fragments; combination approaches under study
Safety Profile
Investigational research protein. No human dosing data. Recombinant endorepellin tolerated in mouse studies at tested doses. No approved therapeutic product.
Legal & Regulatory
Research use only
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