Insulin-like growth factor I is required for vessel remodeling in the adult brain

Abstract

Although vascular dysfunction is a major suspect in the etiology of several important neurodegenerative diseases, the signals involved in vessel homeostasis in the brain are still poorly understood. We have determined whether insulin-like growth factor I (IGF-I), a wide-spectrum growth factor with angiogenic actions, participates in vascular remodeling in the adult brain. IGF-I induces the growth of cultured brain endothelial cells through hypoxiainducible factor 1␣ and vascular endothelial growth factor, a canonical angiogenic pathway. Furthermore, the systemic injection of IGF-I in adult mice increases brain vessel density. Physical exercise that stimulates widespread brain vessel growth in normal mice fails to do so in mice with low serum IGF-I. Brain injury that stimulates angiogenesis at the injury site also requires IGF-I to promote perilesion vessel growth, because blockade of IGF-I input by an anti-IGF-I abrogates vascular growth at the injury site. Thus, IGF-I participates in vessel remodeling in the adult brain. Low serum͞brain IGF-I levels that are associated with old age and with several neurodegenerative diseases may be related to an increased risk of vascular dysfunction.

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging

“…Our findings, taken together with results of previous studies obtained in mice with developmental liver-specific knockdown of IGF-1 (Lopez-Lopez et al 2004), suggest that circulating level of IGF-1 is a critical regulator of brain capillarity. These findings are clinically relevant as circulating IGF-1 levels significantly decrease with age in humans (Franco et al 2014;O'Connor et al 1998), and restoration of circulating IGF-1 in older laboratory animals was shown to significantly increase cerebromicrovascular density (Sonntag et al 1997).…”

“…Early studies on decreased capillary density in the peripheral circulation of hypertensive experimental animals and human patients proposed that rarefaction can be either structural (capillary attrition) or functional, associated with impaired recruitment of nonperfused capillaries (Chen et al 1981;Hashimoto et al 1987;Ono et al 1989;Prewitt et al 1986;Prewitt et al 1982;Prewitt et al 1984;Stacy and Prewitt 1989;Sullivan et al 1983). Our studies provide additional evidence that interaction of IGF-1 deficiency and hypertension promote structural rarefaction in the mouse brain, extending previous findings obtained in hypertensive patients (Wolf et al 1994;Bell and Ball 1981;Bell and Ball 1990;Abernethy et al 1993;Mann et al 1986) and animal models of aging (Sonntag et al 1997;Wiesenborn et al 2014), hypertension (Toth et al 2013a) and IGF-1 deficiency (Lopez-Lopez et al 2004), but further studies are needed to understand their synergistic effects on the cerebral microvasculature.…”

“…Furthermore, previous studies demonstrate that treatment of mice with IGF-1 results in formation of new capillaries in the mouse brain (Lopez-Lopez et al 2004). Our data suggest that hypertension also results in dysregulated expression of pro-and anti-angiogenic genes, and these effects tend to be exacerbated by IGF-1 deficiency.…”

“…Principally, the agerelated decline in circulating levels of insulin-like growth factor-1 (IGF-1) has been linked to microvascular aging and cognitive decline (reviewed recently in ). IGF-1, which is secreted mainly by the liver and mediates the actions of growth hormone, is a pleiotropic growth factor which confers multifaceted proangiogenic effects, regulating microvascular remodeling (Lopez-Lopez et al 2004) and protection against endothelial injury (Bailey-Downs et al 2012a;Bailey-Downs et al 2012b). We have recently demonstrated that mice with isolated decreases of circulating IGF-1 levels exhibit aging-like microvascular phenotypes, including impaired neurovascular coupling and cerebromicrovascular autoregulatory dysfunction (Lopez-Lopez et al 2004;Toth et al 2015;Toth et al 2014a).…”

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

“…This process is triggered by a protease which cleaves IGF-I from its dominating binding protein IGFBP-3, allowing free IGF-I to enter the endothelial barrier, using specific transport proteins (18). Furthermore, systemic administration of IGF-I modulates brain vessel growth and cognitive function in mice, suggesting a link between circulatory derived IGF-I and IGF-I within the brain (19,20).…”