The angiotensin II receptor type 1b is the primary sensor of intraluminal pressure in cerebral artery smooth muscle cells.
J Physiol
; 595(14): 4735-4753, 2017 07 15.
Article
em En
| MEDLINE
| ID: mdl-28475214
ABSTRACT
KEY POINTS The angiotensin II receptor type 1b (AT1 Rb ) is the primary sensor of intraluminal pressure in cerebral arteries. Pressure or membrane-stretch induced stimulation of AT1 Rb activates the TRPM4 channel and results in inward transient cation currents that depolarize smooth muscle cells, leading to vasoconstriction. Activation of either AT1 Ra or AT1 Rb with angiotensin II stimulates TRPM4 currents in cerebral artery myocytes and vasoconstriction of cerebral arteries. The expression of AT1 Rb mRNA is â¼30-fold higher than AT1 Ra in whole cerebral arteries and â¼45-fold higher in isolated cerebral artery smooth muscle cells. Higher levels of expression are likely to account for the obligatory role of AT1 Rb 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 (AT1 R) is inherently mechanosensitive and initiates this signalling pathway. Rodents express two types of AT1 R - AT1 Ra and AT1 Rb - and conflicting studies provide support for either isoform as the primary sensor of intraluminal pressure in peripheral arteries. We hypothesized that mechanical activation of AT1 Ra increases TRPM4 currents to induce myogenic constriction of cerebral arteries. However, we found that development of myogenic tone was greater in arteries from AT1 Ra 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 AT1 R blocker losartan (1 µm) diminished myogenic tone and blocked stretch-induced cation currents in cerebral arteries from both groups. Activation of AT1 R with angiotensin II (30 nm) also increased TRPM4 currents in smooth muscle cells and constricted cerebral arteries from both groups. Expression of AT1 Rb mRNA was â¼30-fold greater than AT1 Ra in cerebral arteries, and knockdown of AT1 Rb selectively diminished myogenic constriction. We conclude that AT1 Rb , acting upstream of TRPM4 channels, is the primary sensor of intraluminal pressure in cerebral artery smooth muscle cells.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artérias Cerebrais
/
Miócitos de Músculo Liso
/
Receptor Tipo 1 de Angiotensina
Limite:
Animals
Idioma:
En
Revista:
J Physiol
Ano de publicação:
2017
Tipo de documento:
Article