Pulsatile stretch as a novel modulator of amyloid precursor protein processing and associated inflammatory markers in human cerebral endothelial cells.

Amyloid ß (Aß) deposition is a hallmark of Alzheimer's disease (AD). Vascular modifications, including altered brain endothelial cell function and structural viability of the blood-brain barrier due to vascular pulsatility, are implicated in AD pathology. Pulsatility of phenomena in the cerebral vasculature are often not considered in in vitro models of the blood-brain barrier. We demonstrate, for the first time, that pulsatile stretch of brain vascular endothelial cells modulates amyloid precursor protein (APP) expression and the APP processing enzyme, ß-secretase 1, eventuating increased-Aß generation and secretion. Concurrent modulation of intercellular adhesion molecule 1 and endothelial nitric oxide synthase (eNOS) signaling (expression and phosphorylation of eNOS) in response to pulsatile stretch indicates parallel activation of endothelial inflammatory pathways. These findings mechanistically support vascular pulsatility contributing towards cerebral Aß levels.

Mechanical stretch: physiological and pathological implications for human vascular endothelial cells.

Vascular endothelial cells are subjected to hemodynamic forces such as mechanical stretch due to the pulsatile nature of blood flow. Mechanical stretch of different intensities is detected by mechanoreceptors on the cell surface which enables the conversion of external mechanical stimuli to biochemical signals in the cell, activating downstream signaling pathways. This activation may vary depending on whether the cell is exposed to physiological or pathological stretch intensities. Substantial stretch associated with normal physiological functioning is important in maintaining vascular homeostasis as it is involved in the regulation of cell structure, vascular angiogenesis, proliferation and control of vascular tone. However, the elevated pressure that occurs with hypertension exposes cells to excessive mechanical load, and this may lead to pathological consequences through the formation of reactive oxygen species, inflammation and/or apoptosis. These processes are activated by downstream signaling through various pathways that determine the fate of cells. Identification of the proteins involved in these processes may help elucidate novel mechanisms involved in vascular disease associated with pathological mechanical stretch and could provide new insight into therapeutic strategies aimed at countering the mechanisms' negative effects.

Estrogen signaling through estrogen receptor beta and G-protein-coupled estrogen receptor 1 in human cerebral vascular endothelial cells: implications for cerebral aneurysms.

Little is known about estrogen receptors and their signaling mechanisms in human cerebral vascular endothelial cells, which is important for understanding cerebral aneurysm pathogenesis in menopausal and postmenopausal women. Estrogen receptor beta (ERß) and G-protein-coupled receptor 1 (GPER1) were immunocytochemically identified in human cerebral vascular endothelial cells (HCVECs). ERß was mainly located at the nuclei of the cells while GPER1 was located at the plasma membrane. Interaction events between 17ß-estradiol and ERß or GPER1 in HCVECs were evaluated by in situ proximity ligation assay. The number of interaction events between 17ß-estradiol and ERß was positively correlated with 17ß-estradiol concentrations (r = 0.9614, P < 0.01). The interaction events between 17ß-estradiol and GPER1 were dose responsive. Our data support HCVECs to serve as a suitable cellular model for studying cerebral aneurysm pathogenesis in menopausal and postmenopausal women. Subtypes of estrogen receptors and their signaling mechanisms identified in HCVECs could be applicable for developing estrogen-like compounds to specifically bind to a subtype of estrogen receptors with greater specific action on the cerebral arteries, without the estrogen-dependent side effects on the reproductive organs, to prevent cerebral aneurysm formation in menopausal and postmenopausal woman.