Endothelium- selective overexpression of p25 results in impaired smooth muscle-dependent vascular function, altered...

The role of P25 is dual, acting as a critical, transient regulator in normal memory formation, but also causes patological effect as a neurotoxic agent when activated chronically in neurodegenerative diseases. However, the role of CDK5/p25 signaling in endothelium has not been established. Here, we assessed the effect of selective endothelial overactivation of p25, the major regulator of the CDK5 on vascular function. In transgenic mouse model with selective overexpression of P25 in vascular endothelial cells (EC-p25) endothelial and smooth muscle function was characterized in vivo using unique MRI-based analysis, with accompanying molecular and biochemical assays in isolated vessels and endothelial cells. In young 12-20 week-old EC-p25 mice Ach-induced vasodilation measured in vivo by MRI was lost and changed into vasoconstriction. Flow-mediated vasodilation (FMD) was progressively impaired in 12-20 week-old EC-p25 mice. SNP-induced vasodilation was also profoundly impaired. Moreover, it was associated with vascular smooth muscle cells (VSMC) remodeling including hyperplasia and hypertrophy of smooth muscle cells as well as deposition of extracellular matrix (ECM). Nitric oxide production in aorta ex vivo assessed by EPR, NOS expression assessed by immunohistological staining, as well systemic NO bioavailability assessed based on nitrite and nitrate plasma concentration measured by HPLC were all not significantly changed in 12-20 week-old EC-p25 mice. However, aorta from 20-week-old EC-p25 mice displayed diminished α-SMA and sGC expression. In conclusion, endothelium-specific p-25 overexpression resulted in impaired smooth muscle - dependent vascular function and altered sGC-dependent pathway that was correlated with altered structure of aortic wall. Altogether, the overexpression of p-25 -dependent endothelial signaling resulted in dysregulation of VSMC structure and function highlighting disturbance in EC-VSMC communication.