Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension.

Abstract

Hypertension in the elderly substantially contributes to cerebromicrovascular damage and promotes the development of vascular cognitive impairment. Despite the importance of the myogenic mechanism in cerebromicrovascular protection, it is not well understood how aging affects the functional adaptation of cerebral arteries to high blood pressure. Hypertension was induced in young (3 months) and aged (24 months) C57/BL6 mice by chronic infusion of angiotensin II (AngII). In young hypertensive mice, the range of cerebral blood flow autoregulation was extended to higher pressure values, and the pressure-induced tone of middle cerebral artery (MCA) was increased. In aged hypertensive mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In young mice, the mechanism of adaptation to hypertension involved upregulation of the 20-HETE (20-hydroxy-5,8,11,14-eicosatetraenoic acid)/transient receptor potential cation channel, subfamily C (TRPC6) pathway and this mechanism was impaired in aged hypertensive mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in aged AngII-induced hypertensive mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal dependent cognitive function. Collectively, aging impairs autoregulatory protection in the brain of mice with AngII-induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation.

• Authors: Peter Toth, Zsuzsanna Tucsek, Danuta Sosnowska, Tripti Gautam, Matthew Mitschelen, Stefano Tarantini, Ferenc Deak, Akos Koller, William E Sonntag, Anna Csiszar, Zoltan Ungvari
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 33 Issue 11 Pg. 1732-42 (Nov 2013) ISSN: 1559-7016 [Electronic] United States
• PMID: 23942363 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acta2 protein, mouse
• Actins
• Cytokines
• Hydroxyeicosatetraenoic Acids
• TRPC Cation Channels
• TRPC6 Cation Channel
• Trpc6 protein, mouse
• Angiotensin II
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid

Topics

• Actins (genetics)
• Adaptation, Physiological
• Aging (metabolism, pathology)
• Angiotensin II (pharmacology)
• Animals
• Behavior, Animal (physiology)
• Blood-Brain Barrier (metabolism, pathology)
• Cerebrovascular Circulation (physiology)
• Cytokines (biosynthesis)
• Disease Models, Animal
• Hydroxyeicosatetraenoic Acids (biosynthesis)
• Hypertension (chemically induced, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microvessels (pathology, physiopathology)
• Middle Cerebral Artery (pathology, physiopathology)
• TRPC Cation Channels (biosynthesis)
• TRPC6 Cation Channel
• Up-Regulation