Isolated Human and Rat Cerebral Arteries Constrict to Increases in Flow: Role of 20-HETE and TP Receptors

Abstract

Elevation of intraluminal pressure increases vasomotor tone, which thought to have a substantial role in regulation of cerebral blood flow (CBF). Interestingly, responses of cerebral vessels to increases in flow varied and have not been studied in human cerebral arteries. We hypothesized that increases in flow elicit constrictions of isolated human and rat cerebral arteries and aimed to elucidate the underlying mechanisms. Human cerebral arteries and rat middle cerebral arteries constricted to increases in flow (P < 0.05). Simultaneous increase in intraluminal flow + pressure further reduced the diameter compared with pressure-induced changes (P < 0.05), leading to constant estimated CBF. Flow-induced constrictions were abolished by HET0016 (inhibitor of synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) or inhibition of COXs or blocking TP (thromboxane A 2 /prostaglandin H 2 , receptors and attenuated by scavenging reactive oxygen species (ROS). Flow-enhanced ROS formation was significantly reduced by HET0016. In conclusion, in human and rat cerebral arteries (1) increases in flow elicit constrictions, (2) signaling mechanism of flow-induced constriction of cerebral arteries involves enhanced production of ROS, COX activity, and mediated by 20-HETE via TP receptors, and (3) we propose that simultaneous operation of pressure-and flow-induced constrictions is necessary to provide an effective autoregulation of CBF.

Dietary Omega-3 Polyunsaturated Fatty Acids Prevent Vascular Dysfunction and Attenuate Cytochrome P4501A1 Expression by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin

“…Vascular overproduction of 20-HETE decreases endothelial-dependent vasodilation, and increases oxidative stress, vasoconstriction and blood pressure (Wang et al, 2006). Furthermore, vasoconstriction by 20-HETE is mediated by activation of TP receptor in many vascular beds Muller et al, 2007;Schwartzman et al, 1989;Toth et al, 2011), including the mouse aorta as shown by our results. We also found that TCDD increases the contribution of the TP receptor to AA-mediated vasoconstriction, further implicating the potential contribution of 20-HETE to TCDDinduced vascular dysfunction.…”

“…As noted earlier 20-HETE is predominately generated by CYP4A12 in male mice and in some vascular beds vasoconstriction by 20-HETE is dependent on subsequent cyclooxygenase metabolism to a TP receptor agonist Muller et al, 2007;Schwartzman et al, 1989;Toth et al, 2011). Thus, the mRNA expression of Cyp4a12 in the liver and kidney, and prostaglandin-endoperoxide synthase 2 (aka cyclooxygenase 2) was analyzed in the lung, representing the tissues where they are predominately expressed.…”

Role of 20-HETE, TRPC channels, and BKCa in dysregulation of pressure-induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice

“…On day 28 postimplantation mice were decapitated, the brains were removed, and segments of the MCAs were isolated using microsurgery instruments for functional studies, as reported (59,64). Segments of MCAs were mounted onto two glass micropipettes in an organ chamber in oxygenated (21% O 2-5% CO2-75% N2) Krebs= buffer (pH ϭ 7.4) and pressurized to 60 mmHg.…”

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Induces Relaxations of Peripheral and Cerebral Arteries, which are Differentially Impaired by Aging

“…The vessels were isolated as previously described (Vamos et al 2013 ;Toth et al 2011 ). In brief, animals were anesthetized by intraperitoneal ketamin and decapitated immediately.…”