English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT

Released

Journal Article

Loss of Endothelial Cytochrome P450 Reductase Induces Vascular Dysfunction in Mice

MPS-Authors
/persons/resource/persons251576

Lopez,  Melina
IMPRS, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons251610

Warwick,  Timothy
IMPRS, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons251645

Oo,  James
IMPRS, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224128

Guenther,  Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

External Resource
No external resources are shared
Fulltext (restricted access)
There are currently no full texts shared for your IP range.
Fulltext (public)
There are no public fulltexts stored in PuRe
Supplementary Material (public)
There is no public supplementary material available
Citation

Malacarne, P. F., Ratiu, C., Gajos-Draus, A., Mueller, N., Lopez, M., Pflueger-Mueller, B., et al. (2022). Loss of Endothelial Cytochrome P450 Reductase Induces Vascular Dysfunction in Mice. HYPERTENSION, 79(6), 1216-1226. doi:10.1161/HYPERTENSIONAHA.121.18752.


Cite as: http://hdl.handle.net/21.11116/0000-000A-830A-7
Abstract
Background: POR (cytochrome P450 reductase) provides electrons for the catalytic activity of the CYP (cytochrome P450) monooxygenases. CYPs are dual-function enzymes as they generate protective vasoactive mediators derived from polyunsaturated fatty acids but also reactive oxygen species. It is not known in which conditions the endothelial POR/CYP system is beneficial versus deleterious. Here, the activity of all CYP enzymes was eliminated in the vascular endothelium to examine its impact on vascular function. Methods: An endothelial-specific, tamoxifen-inducible POR knockout mouse (ecPOR(-)(/-)) was generated. Vascular function was studied by organ chamber experiments. eNOS (endothelial nitric oxide synthase) activity was accessed by heavy arginine/citrulline LC-MS/MS detection and phosphorylation of serine1177 in aortic rings. CYP-derived epoxyeicosatrienoic acids and prostanoids were measured by LC-MS/MS. Gene expression of aorta and endothelial cells was profiled by RNA sequencing. Blood pressure was measured by telemetry. Results: Acetylcholine-induced endothelium-dependent relaxation was attenuated in isolated vessels of ecPOR(-/-) as compared with control mice. Additionally, ecPOR(-/-) mice had attenuated eNOS activity and eNOS/AKT phosphorylation. POR deletion reduced endothelial stores of CYP-derived epoxyeicosatrienoic acids but increased vascular prostanoids. This phenomenon was paralleled by the induction of genes implicated in eicosanoid generation. In response to Ang II (angiotensin II) infusion, blood pressure increased significantly more in ecPOR(-)(/-) mice. Importantly, the cyclooxygenase inhibitor Naproxen selectively lowered the Ang II-induced hypertension in ecPOR(-)(/-) mice. Conclusions: POR expression in endothelial cells maintains eNOS activity and its loss results in an overactivation of the vasoconstrictor prostanoid system. Through these mechanisms, loss of endothelial POR induces vascular dysfunction and hypertension.