Inhibition of 20‐HETE Production Attenuates Cerebral Blood Flow Autoregulation on Rat Brain Surface and Deep Cortex.

R1636 --> 20‐HETE is a metabolite of arachidonic acid produced by enzymes of CYP4A and CYP4F families. We previously reported that Dahl S rats have a genetic deficiency in the production of 20‐HETE and the expression of CYP4A enzymes and exhibit impaired myogenic response of the middle cerebral artery (MCA) and autoregulation of cerebral blood flow (CBF) but the mechanism is unknown. The present study explored whether 20‐HETE has direct effects on the regulation of cerebral mural cell contractility that may play an essential role in autoregulation of CBF in the surface and deep cortex. We found that CYP4A was expressed in vascular smooth muscle cells (VSMCs) and pericytes along parenchymal arteries and capillaries isolated from the MCA territory of SD rats. Gel size was reduced to a lesser extent in VSMCs treated with the 20‐HETE synthesis inhibitor, HET0016 (10 μM) versus vehicle (17.9 ± 0.5 % vs. 28.3 ± 0.5 %; n = 9), indicating loss of contractility. Similarly, constriction of cerebral pericytes treated with HET0016 was reduced relative to controls. Cell contractile capability of cerebral VSMC and pericyte collaboratively play a role in regulating CBF in the superficial and deep cortex of the brain by modulation of the myogenic response of the MCA and arterioles, respectively. CBF was well autoregulated in the surface and deep cortex in SD rats and only increased by 12.9 ± 1.7 % and 13.3 ± 1.9 %, respectively, when pressure was elevated from 100 to 140 mmHg. In contrast, CBF increased by 34.6 ± 3.2 % and 28.5 ± 2.3 %, respectively after the rats were given HET0016 (2 mg/kg). These results demonstrate that CYP4A is expressed both in VSMC and pericytes of parenchymal arteries and capillaries, that blockade of 20‐HETE reduces the contractile activity of these cells and attenuates autoregulation of CBF in the superficial and deep cortex of the brain. They provide novel insight into human genetic studies indicating that inactivate variants of 20‐HETE producing enzymes are associated with a higher incidence of hypertension, stroke, and AD. [ABSTRACT FROM AUTHOR]