The angiotensin II receptor type 1b is the primary sensor of intraluminal pressure in cerebral artery smooth muscle cells

Abstract

The angiotensin II receptor type 1b (AT R ) is the primary sensor of intraluminal pressure in cerebral arteries. Pressure or membrane-stretch induced stimulation of AT R activates the TRPM4 channel and results in inward transient cation currents that depolarize smooth muscle cells, leading to vasoconstriction. Activation of either AT R or AT R with angiotensin II stimulates TRPM4 currents in cerebral artery myocytes and vasoconstriction of cerebral arteries. The expression of AT R mRNA is ∼30-fold higher than AT R in whole cerebral arteries and ∼45-fold higher in isolated cerebral artery smooth muscle cells. Higher levels of expression are likely to account for the obligatory role of AT R for pressure-induced vasoconstriction ABSTRACT: Myogenic vasoconstriction, which reflects the intrinsic ability of smooth muscle cells to contract in response to increases in intraluminal pressure, is critically important for the autoregulation of blood flow. In smooth muscle cells from cerebral arteries, increasing intraluminal pressure engages a signalling cascade that stimulates cation influx through transient receptor potential (TRP) melastatin 4 (TRPM4) channels to cause membrane depolarization and vasoconstriction. Substantial evidence indicates that the angiotensin II receptor type 1 (AT R) is inherently mechanosensitive and initiates this signalling pathway. Rodents express two types of AT R - AT R and AT R - and conflicting studies provide support for either isoform as the primary sensor of intraluminal pressure in peripheral arteries. We hypothesized that mechanical activation of AT R increases TRPM4 currents to induce myogenic constriction of cerebral arteries. However, we found that development of myogenic tone was greater in arteries from AT R knockout animals compared with controls. In patch-clamp experiments using native cerebral arterial myocytes, membrane stretch-induced cation currents were blocked by the TRPM4 inhibitor 9-phenanthrol in both groups. Further, the AT R blocker losartan (1 μm) diminished myogenic tone and blocked stretch-induced cation currents in cerebral arteries from both groups. Activation of AT R with angiotensin II (30 nm) also increased TRPM4 currents in smooth muscle cells and constricted cerebral arteries from both groups. Expression of AT R mRNA was ∼30-fold greater than AT R in cerebral arteries, and knockdown of AT R selectively diminished myogenic constriction. We conclude that AT R , acting upstream of TRPM4 channels, is the primary sensor of intraluminal pressure in cerebral artery smooth muscle cells.

Neuroprotective effects of TRPA1 channels in the cerebral endothelium following ischemic stroke

“…Arteries were then washed three times with Ca 2+ -free PSS and incubated in tissue-collection solution supplemented with 1 mg/mL type II collagenase (Worthington Biochemical Company) for 12 min in a 37°C water bath. Thereafter, arteries were washed three times with PSS and triturated by passing the solution through a fire-polished glass Pasteur pipette, as described previously ( Pires et al, 2015 ; Pires et al, 2017 ). Dissociated cells in the solution were placed in a 35 mm glass-bottom dish (Greiner Bio-One GmBH, Germany) and allowed to adhere to the dish for 30 min in a cell culture incubator.…”

Eicosanoids and Oxidative Stress in Diabetic Retinopathy

“…Ang I is then hydrolyzed by angiotensin-converting enzyme (ACE) to produce Angiotensin II (Ang II) [ 108 , 109 ]. Ang II is the major bioactive product of RAS, and Ang II receptor type 1 (AT1 receptor) is the primary receptor to mediate the function of Ang II [ 117 , 118 , 119 , 120 ]. Several clinical studies are designed to determine the effects of RAS blockade in the development of DR because RAS activation is implicated in DR development in animal studies [ 108 , 109 , 110 , 111 , 112 ].…”

Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries

“…Species differences may also contribute when considering the role of specific AT 1 R subtypes. For example, rodents express two AT 1 R subtypes while humans have only one subtype 48 and within rodents there is currently disparate findings as to the relative importance of the AT 1a R and AT 1b R 8, 19, 25, 49 (and current results). In addition, the current studies have not considered interactions between mechano- and agonist-induced activation of the AT 1 R and how this may impact RGS5 mediated signaling.…”