SUMMARY:
UCLA researchers in the department of medicine have discovered that suppressing SOX2 in the vascular endothelium improves lumen disorder thereby, inhibiting vascular calcification and cerebral arteriovenous malformations (AVMs).
BACKGROUND:
AVMs can form in multiple organs randomly or due to genetic diseases. AVMs have high tendencies to cause uncontrolled bleeding or hemorrhage. Depending upon the location, AVMs can cause hemorrhagic strokes, pulmonary and gastrointestinal bleedings. Cerebral AVMs are abnormal connections between arteries and veins that disallow oxygen diffusion into surrounding tissues thereby, disrupting normal blood flow. Additionally, the abnormal vessels frequently leak and rupture, causing further tissue injuries.
Disruptions in the integrity of the vascular endothelium and/or endothelial cell (EC) differentiation are primarily, implicated in the formation of cerebral AVMs. The amount of blood circulated to different tissues is dependent upon the lumen size of different blood vessels. Lumen integrity and vascular homeostasis is maintained by fully differentiated ECs, arranged in a single layer that interface between the vascular wall and blood stream. Improper differentiation of these ECs is a major contributor of vascular pathogenesis.
Endothelial Sry-box 2 (SOX2) is a transcription factor was recently implicated in multiple vascular disease states such as vascular calcification (VC), atherosclerosis, diabetes and cerebral AVMs. Pathogenic stimuli induce Sox2 within the vascular lining thereby, converting normal vascular lining to a diseased state i.e., endothelial-mesenchymal transitions (EndMTs), which cause aberrations in the lumen formation or “lumen disorder” in cerebral AVMs.
Current treatments for AVMs in the brain typically involve surgery or radiation, but the location and size of the AVM can make both options unviable. Thus, SOX2 suppression to maintain the state of quiescence in the vascular lining, preventing it from eliciting vascular malformations in is an attractive therapeutic strategy.
INNOVATION:
UCLA researchers led by Dr. Yucheng Yao have identified that EC-specific suppression of Sox2 normalized endothelial differentiation and lumen formation thus, improving the cerebral AVMs. Through epigenetic studies, they found that Sox2 altered the cerebral EndMTs through jumonji domain–containing protein 5 (JMJD5). Furthermore, they conducted a high-throughput screening assay and identified the β-adrenergic antagonist pronethalol as an inhibitor of Sox2 expression. Treatment with pronethalol stabilized endothelial differentiation and lumen formation, which limited the cerebral AVMs.
POTENTIAL APPLICATIONS:
- Treatment of AVMs
- Treatment of vascular calcification
- Potential treatment of other vascular disorders
ADVANTAGES:
- Non-invasive treatment option for AVM and vascular calcification.
- Allows preventative treatment for stroke and clotting induced by AVM or vascular calcification throughout the body
DEVELOPMENT-TO-DATE:
The UCLA research team has identified several suppresses of SOX2 protein including one small molecule, pronethalol which has also been demonstrated effective at treating vascular calcification and AVMs in mice.
Related Papers (from the inventors only)
- Yao, J. et al. Serine Protease Activation Essential for Endothelial–Mesenchymal Transition in Vascular Calcification. Circ Res 117, 758–769 (2015).
- Yao, J. et al. Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations. Journal of Clinical Investigation 129, 3121–3133 (2019).
- Yao, Y. et al. A Role for the Endothelium in Vascular Calcification. Circ Res 113, 495–504 (2013).
- Qiao, Xiaojing, et al. “Pronethalol Decreases RBPJκ to Reduce Sox2 in Cerebral Arteriovenous Malformation.” Vascular Medicine (United Kingdom), vol. 25, no. 6, 2020, pp. 569–71, doi:10.1177/1358863X20942833.