IGF‐1 deficiency alters hypertension induced cerebrovascular remodeling in mice

Abstract

Hypertension induced cerebral microhemorrhages (CMHs) may contribute to cognitive decline and predict larger strokes. Previous studies of our group found evidence that IGF‐1 deficiency exacerbates hypertension‐induced cerebral microhemorrhages (CMHs) mimicing an age‐related phenotype, but the underlying mechanisms remain elusive. We hypothesized that increased cerebrovascular stiffness and altered hypertension induced remodeling of the vessels may contribute to higher number of CMHS in IGF‐1 deficiency. Liver‐specific knockdown of IGF‐1 (Igf1f/f + TBG‐iCre‐AAV8) and control mice were chronically treated with angiotensin‐IIleading to similar hypertension in both groups (CTRL syst.: 151.375±2.08, diast.:109.65±3.27; IGF syst.: 150.10±2.00, diast.: 106.48±2.53). Middle cerebral (MCA) arteries of both groups were examined, by fixing them to a canulated isobaric vascular system and loaded with calcein. Smooth muscle cell related characteristics likepressure induced alteration in wall thickness and vessel diameter were measured using confocal microscopy. We found impaired cellular hypertrophic response in the IGF‐1 deficient hypertensive (HT) group, leading to smaller increase in wall thickness (1.43±0.04 μm in CTRL HT vs. 1.25±0.04 μm in IGF‐1 deficient HT). Based on the wall thickness and vessel diameter data circumferential stress and circumferential strain were calculated at different pressure levels (5–160 mmHg). Circumferential stress was higher in the IGF‐1 deficient group at any given pressure comparing to wild type group, while there was no change in the circumferential strain. Young's elastic modulus (Emod) was calculated by linear fitting of the stress‐strain curve. The Emod at lower pressures (describes elastin based elasticity) was higher in IGF‐1 HT group (468.20±73.56 vs. 306.77±36.22) while there was no change in the Emod at higher pressures (describes collagen based elasticity). Based on these data we can conclude that age‐related IGF‐1 deficiency alters hypertension‐induced cellular and extracellular matrix remodeling, which may lead to increased stiffnening of microvessels, possibly leading to incrased risk of pressure‐induced rupture.Support or Funding InformationThis work was supported by grants from the American Heart Association, the National Center for Complementary and Alternative Medicine, and the National Institute on Aging