Premium
IGF‐1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice (1079.2)
Author(s) -
Toth Peter,
Tucsek Zsuzsanna,
Tarantini Stefano,
Sosnowska Danuta,
Gautam Tripti,
Mitschelen Matthew,
Koller Akos,
Sonntag William,
Csiszar Anna,
Ungvari Zoltan
Publication year - 2014
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.28.1_supplement.1079.2
Subject(s) - autoregulation , neuroinflammation , medicine , endocrinology , angiotensin ii , cerebral autoregulation , cerebral blood flow , blood pressure , homeostasis , cerebral circulation , inflammation
Aging impairs autoregulatory protection in the brain, exacerbating hypertension‐induced cerebromicrovascular injury, neuroinflammation and development of vascular cognitive impairment (VCI). Despite the paramount importance of the age‐related decline in circulating insulin‐like growth factor‐1 (IGF‐1) levels in brain and cerebrovascular aging, it is not well understood how IGF‐1 deficiency affects the functional adaptation of cerebral arteries to high blood pressure. To test the hypothesis that IGF‐1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF‐1 deficient mice (AAV knockdown of hepatic IGF‐1 [ Igf1 f/f + MUP‐iCre‐AAV8]) by chronic infusion of angiotensin II and changes in autoregulation of cerebral blood flow andmyogenic constriction of middle cerebral arteries (MCA) were assessed. In hypertensive control mice, the range of cerebral blood flow autoregulation was extended to higher pressure values and the pressure‐induced tone of MCA was increased. In hypertensive IGF‐1 deficient mice autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice the mechanism of adaptation to hypertension involved up‐regulation of a TRPC channel‐dependent pathway and this mechanism was impaired in hypertensive IGF‐1 deficient mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF‐1 deficient mice included exacerbated disruption of the blood‐brain barrier and neuroinflammation (microglia activation, up‐regulation of pro‐inflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF‐1 deficiency impairs autoregulatory protection in the brain of mice with angiotensin II‐induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype. Grant Funding Source : Supported by the Nemzeti Fejlesztési Ügynökség and NIH