Angioneurins–key regulators of blood-brain barrier integrity during hypoxic and ischemic brain injury

YOU are going to have to setup followup research since nothing will get done otherwise.  Might improve is a useless term. The mentors and senior researchers should be fired for allowing such weasel words.  We need stroke protocols, not words.

Angioneurins–key regulators of blood-brain barrier integrity during hypoxic and ischemic brain injury

Author links open overlay panelReinerKunze

Hugo H.Marti

https://doi.org/10.1016/j.pneurobio.2019.03.004Get rights and content

Abstract

The loss of blood-brain barrier (BBB) integrity leading to vasogenic edema and brain swelling is a common feature of hypoxic/ischemic brain diseases such as stroke, but is also central to the etiology of other CNS disorders. In the past decades, numerous proteins, belonging to the family of angioneurins, have gained increasing attention as potential therapeutic targets for ischemic stroke, but also other CNS diseases attributed to BBB dysfunction. Angioneurins encompass mediators that affect both neuronal and vascular function. Recently, increasing evidence has been accumulated that certain angioneurins critically determine disease progression and outcome in stroke among others through multifaceted effects on the compromised BBB. Here, we will give a concise overview about the family of angioneurins. We further describe the most important cellular and molecular components that contribute to structural integrity and low permeability of the BBB under steady-state conditions. We then discuss BBB alterations in ischemic stroke, and highlight underlying cellular and molecular mechanisms. For the most prominent angioneurin family members including vascular endothelial growth factors, angiopoietins, platelet-derived growth factors and , we will summarize current scientific literature from experimental studies in animal models, and if available from clinical trials, on the following points: (i) spatiotemporal expression of these factors in the healthy and hypoxic/ischemic CNS, (ii) impact of loss- or gain-of-function during cerebral hypoxia/ischemia for BBB integrity and beyond, and (iii) potential underlying molecular mechanisms. Moreover, we will highlight novel therapeutic strategies based on the activation of endogenous angioneurins that might improve BBB dysfuntion during ischemic stroke.

Keywords

Angiopoietin

Blood-brain barrier

Erythropoietin

Hypoxia

Stroke

Vascular endothelial growth factor

Abbreviations

AJ

adherens junction

Ang

angiopoietin

Angptl

angiopoietin-like protein

BBB

blood-brain barrier

BMEC

brain microvascular endothelial cells

Cav-1

caveolin-1

CNS

central nervous system

EB

Evans blue

ECM

extracellular matrix

Epo

erythropoietin

HIF

hypoxia-inducible transcription factor

JAM

junctional adhesion molecule

MCAO

middle cerebral artery occlusion

MMP

matrix metalloproteinase

NVU

neurovascular unit

PDGF

platelet-derived growth factor

PHD

prolyl-4-hydroxylase domain

PI3-K

phosphatidylinositol 3-kinase

rtPA

recombinant tissue plasminogen activator

SMC

smooth muscle cell

SVZ

subventricular zone

Tie

tyrosine kinase with immunoglobulin and epidermal growth factor homology domain

TJ

tight junction

VE-cadherin

vascular endothelial cadherin

VEGF

vascular endothelial growth factor

ZO

Zona occludens