The (patho)physiological role(s) of CYP450-mediated mechanism(s) in the ophthalmic artery

• Applicant: Dr. Caroline Manicam
• Subject Area: Ophthalmology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397969102

While the vascular-related risk factor is not a new concept in the pathogenesis of glaucoma, alterations in cell signalling mechanisms and proteome changes underlying perturbed retrobulbar microcirculation, particularly the ophthalmic artery, are still unknown. Our preliminary studies have demonstrated that the cytochrome P450 (CYP450) pathway plays a key role in mediating ophthalmic arterial vasodilatory responses. Therefore, the main aim of this study is to investigate the (patho)physiological roles of the CYP450-mediated signalling or its lack thereof, in the ophthalmic microcirculation by addressing three major hypotheses. To date, the identity, expression and mechanisms of CYP450-derived eicosanoids and potential role of the main metabolizing enzyme of lipid mediators, soluble epoxide hydrolase (sEH), in the regulation of ophthalmic vascular tone and remodelling are uncharacterized. Hence, the first hypothesis is sEH inhibition would confer vasoprotection when exposed to glaucoma-related risk factors and insults by enhancing the bioavailability of CYP450-derived eicosanoids in the ophthalmic artery. This investigation will determine how the CYP450/sEH signalling maintains ophthalmic arterial integrity and what specific pathway(s) and/or mediator(s) are involved. We also demonstrated that this vascular bed possesses inherent compensatory mechanisms that preserve vasodilation when a signalling pathway is impaired. Thus, the second hypothesis to be tested is the ophthalmic artery is able to compensate and retain near-normal vascular responses in chronic lack of CYP450. This investigation will elucidate the underlying proteome, cellular and vascular structural adaptation processes that strive to buffer potential detrimental effects due to the lack of CYP450-mediated signal transduction. The third hypothesis is dietary supplementation with omega-3 fatty acids (ω3-PUFAs) would act as alternative substrates and prevent vascular dysfunction attributed to the chronic lack of CYP450. The findings of this investigation are envisioned to unravel potential shift(s) in the compensatory molecular profiles attributed to PUFAs in the ophthalmic artery. On the other hand, we have also demonstrated that gap junctions work in concert with CYP450 and the Kv1.6 channel is found for the first time to be involved in mediating vasodilatory responses. However, there is still a huge gap in knowledge about the complementary mechanisms involving gap junctional connexins and Kv1.6 channel in this artery. Thus, the final investigation will elucidate the intercellular communication networks of both components and potential alterations in their interactome when CYP450/sEH is lacking. In gist, this study will characterize the (patho)physiological role(s) of CYP450-mediated mechanism(s) in the ophthalmic artery that will facilitate future translational efforts in improving ocular perfusion in glaucoma.

• DFG Programme: Research Grants