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Increased Cerebral Endothelial Transcytosis and Blood‐Brain Barrier Permeability in “Slow Pressor” Angiotensin‐II Hypertension
Author(s) -
Iadecola Costantino,
Faraco Giuseppe,
Lane Diane,
Anrather Josef
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.646.5
Subject(s) - transcytosis , blood–brain barrier , angiotensin ii , medicine , endocrinology , endothelium , endothelial dysfunction , blood pressure , chemistry , central nervous system , receptor , endocytosis
Chronic hypertension (HTN) has deleterious cerebrovascular effects, leading to increased risk of stroke and dementia (AJP 304:H398, 2013). In a the sustained HTN induced by “slow‐pressor” doses of angiotensin‐II (AngII), neurovascular coupling and endothelium‐dependent responses are suppressed. However, the effects of “slow pressor” AngII on the structure and function of the blood‐brain barrier (BBB) remain unclear. Therefore, we examined BBB permeability and ultrastructure in this model of HTN. C57Bl6 male mice were implanted with minipumps delivering saline or AngII (600ng/kg/min). Two weeks later, TRITC‐dextran (4kDa) was administered i.v and the brain conc. of dextran was determined after clearing the intravascular tracer. AngII increased blood pressure (+43±4mmHg; p<0.05; n=8/group) and brain dextran conc. (vehicle: 26±3; AngII: 56±13ng/g; p<0.05). By electron microscopy, slow pressor AngII enhanced endothelial vesicular transcytosis (+80±2%; p<0.05) and reduced by 41±5% the cerebrovascular expression of msfd2a, a BBB‐associated endothelial transmembrane protein that suppresses vesicular transport (Nature 509:507, 2014). Biotinylated AngII, administered i.v. after 2 weeks of AngII, was found in endothelial vesicles, vascular and perivascular cells, and astrocytes. Thus, slow pressor AngII increases BBB permeability. The effect may be due to suppression of msfd2a, leading to enhanced endothelial transcytosis. Circulating AngII crosses the BBB entering perivascular space and brain. Such increase in BBB permeability to circulating agents, including AngII, may contribute to the cerebrovascular and cognitive dysfunction associated with HTN.