Targeting eNOS and beyond: emerging heterogeneity of the role of endothelial Rho proteins in stroke protection

Abstract

Currently available modalities for the treatment of acute ischemic stroke are aimed at preserving or augmenting cerebral blood flow. Experimental evidence suggests that statins, which show 25–30% reduction of stroke incidence in clinical trials, confer stroke protection by upregulation of eNOS and increasing cerebral blood flow. The upregulation of eNOS by statins is mediated by inhibition of small GTP-binding protein RhoA. Our recent study uncovered a unique role for a Rho-family member Rac1 in stroke protection. Rac1 in endothelium does not affect cerebral blood flow. Instead, inhibition of endothelial Rac1 leads to broad upregulation of the genes relevant to neurovascular protection. Intriguingly, inhibition of endothelial Rac1 enhances neuronal cell survival through endothelium-derived neurotrophic factors, including artemin. This review discusses the emerging therapeutic opportunities to target neurovascular signaling beyond the BBB, with special emphasis on the novel role of endothelial Rac1 in stroke protection.

Keywords::

• blood–brain barrier
• eNOS
• GTP-binding protein
• neurotrophic factors
• neurovascular unit
• Rac1
• RhoA
• Rho kinase
• statins
• vascular endothelium

Financial & competing interests/disclosure

This work was supported by grants from the National Institutes of Health (HL052233, HL080187, and NS010828). Naoki Sawada was supported by fellowships from the Uehara Memorial Foundation, the Cell Science Research Foundation and Mochida Memorial Foundation for Medical and Pharmaceutical Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.