Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice

Area of Science:

• Vascular biology
• Molecular genetics
• Neuroscience

Background:

• Cerebral cavernous malformations (CCMs) are CNS vascular lesions with no effective treatments besides surgery.
• Loss-of-function mutations in CCM1, CCM2, or CCM3 disrupt vascular integrity by affecting VE-cadherin.
• VE-cadherin, crucial for endothelial cell junctions, is disorganized in CCM lesions.

Purpose of the Study:

• Investigate the role of microRNA-27a (miR-27a) in CCM pathogenesis.
• Explore miR-27a's regulation by KLF2 and KLF4 in CCM development.
• Evaluate CD5-2, a miR-27a/VE-cadherin interaction blocker, as a potential therapeutic strategy for CCMs.

Main Methods:

• Quantified miR-27a levels in endothelial cells (ECs) from mouse brains with early CCM lesions and in cultured ECs with CCM1/CCM2 depletion.
• Assessed miR-27a's regulatory relationship with KLF2 and KLF4.
• Utilized CD5-2, a target site blocker (TSB), to inhibit miR-27a/VE-cadherin mRNA interaction.
• Evaluated CD5-2's effects on EC monolayer permeability, dermal vessel barrier function, vascular leakage, lesion development, and inflammatory cell accumulation in mouse models.

Main Results:

• miR-27a is elevated in ECs from brains with early CCM lesions and in CCM1/CCM2-depleted ECs.
• miR-27a acts downstream of KLF2 and KLF4.
• CD5-2 treatment reduced EC monolayer permeability and restored dermal vessel barrier function in Ccm1 heterozygous mice.
• In a neonatal mouse model, CD5-2 normalized vasculature, reduced vascular leakage and lesion size, inhibited large lesion development, and decreased inflammatory cell infiltration.

Conclusions:

• VE-cadherin is a viable therapeutic target for normalizing vasculature in CCMs.
• Targeting the miR-27a/VE-cadherin interaction with CD5-2 represents a promising novel therapeutic approach for CCM disease.
• CD5-2 effectively mitigates key pathological features of CCMs in preclinical models.