Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype

Abstract

SummaryClinical and experimental studies show that aging exacerbates hypertension‐induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes insulin‐like growth factor 1 (IGF‐1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF‐1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver‐specific knockdown of IGF‐1 (Igf1 f/f + TBG‐Cre‐AAV8) and control mice by angiotensin II plus l‐NAME treatment. In IGF‐1‐deficient mice, the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Previous studies showed that in aging, increased oxidative stress‐mediated matrix metalloprotease (MMP) activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension‐induced cerebrovascular oxidative stress and MMP activation were increased in IGF‐1‐deficient mice. We found that IGF‐1 deficiency impaired hypertension‐induced adaptive media hypertrophy and extracellular matrix remodeling, which together with the increased MMP activation likely also contributes to increased fragility of intracerebral arterioles. Collectively, IGF‐1 deficiency promotes the pathogenesis of CMHs, mimicking the aging phenotype, which likely contribute to its deleterious effect on cognitive function. Therapeutic strategies that upregulate IGF‐1 signaling in the cerebral vessels and/or reduce microvascular oxidative stress, and MMP activation may be useful for the prevention of CMHs, protecting cognitive function in high‐risk elderly patients.

Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer’s disease

“…There is strong experimental evidence that aging or vascular AD pathologies exacerbate the effects of hypertension on the pathogenesis of CMHs (Ungvari et al 2017b;Toth et al 2015aToth et al , 2017Tarantini et al 2017), worsening the clinical outcome. The cellular and molecular mechanisms by which hypertension promotes CMHs include induction of oxidative stress and MMP activation in the vascular wall, breakdown of the extracellular matrix, pathological structural adaptation to high blood pressure, and/or impairment of myogenic autoregulatory protection, which allows high blood pressure to penetrate the vulnerable distal portion of the cerebral microcirculation (Toth et al 2015a(Toth et al , 2017Tarantini et al 2017;Wakisaka et al 2008Wakisaka et al , 2010. Future studies are needed to identify effective strategies for microvascular protection to prevent the development of CMHs, thereby delaying cognitive decline in AD patients.…”

Transepidermal UV radiation of scalp skin ex vivo induces hair follicle damage that is alleviated by the topical treatment with caffeine

“…Both high and low UVR doses induced a transient up‐regulation of IGF‐1 expression in the ORS at day 1 after exposure (Figure a,c), which may be a compensatory response of the HF against UV‐induced oxidative stress . Long‐term effect (day 3 of organ culture) of UVR resulted in decreased expression of IGF‐1 expression in the HF epithelium but only upon irradiation with the high dose (Figure a,c).…”

Connective tissue growth factor (CTGF) in age-related vascular pathologies

“…The resulting remodeling of the ECM compromises the structural integrity of vascular wall, likely promoting aneurysm formation and aorta dissection/rupture (Meng et al 2014;Muratoglu et al 2013;Wang et al 2006). Upregulation of CTGF may also be involved in the pathogenesis of hypertensioninduced cerebral microhemorrhages by weakening the (Tarantini et al 2017b;Toth et al 2015b;Ungvari et al 2017). CTGF is also expressed in atherosclerotic plaques and is thought to play a role in regulation of plaque stability (Game et al 2007;Ponticos 2013) as well as chemotaxis of leukocytes (Cicha et al 2005).…”