Neuroprotective Effect of Angiopoietin2 Is Associated with Angiogenesis in Mouse Brain Following Ischemic Stroke

Any research that has neuroprotection working in animals should immediately have research conducted in humans. But it won't since we have NO STROKE LEADERSHIP OR STRATEGY!  It's amazingly obvious to everyone but the stroke medical world.

 Neuroprotective Effect of Angiopoietin2 Is Associated withAngiogenesis in Mouse Brain Following Ischemic Stroke

Citation: Lv, L.-L.; Du, Y.-T.; Chen, X.;
Lei, Y.; Sun, F.-Y. Neuroprotective
Effect of Angiopoietin2 Is Associatedwith Angiogenesis in Mouse BrainFollowing Ischemic Stroke. Brain Sci.2022, 12, 1428. https://doi.org/10.3390/brainsci12111428Academic Editors: Kenneth Fong andKunwei WuReceived: 20 September 2022Accepted: 20 October 2022Published: 24 October 2022Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Copyright: © 2022 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).brainsciencesLing-Ling Lv 1,2,†, Yi-Ting Du 1,2,†, Xiao Chen1,2, Yu Lei 1,2 and Feng-Yan Sun 1,2,*1 Department of Neurobiology and State Key Laboratory of Medical Neurobiology, School of Basic MedicalSciences, Shanghai Medical College, Fudan University, Shanghai 200032, China2Institute for Basic Research on Aging and Medicine of School of Basic Medical Sciences and National ClinicalResearch Center for Aging and Medicine, Huashan Hospital, Hanghai Medical College, Fudan University,Shanghai 200032, China* Correspondence: fysun@shmu.edu.cn† These authors contributed equally to this work.

Abstract: 

 Angiogenic factors play an important role in protecting, repairing, and reconstructingvessels after ischemic stroke. In the brains of transient focal cerebral ischemic mice, we observed a reduction in infarct volume after the administration of Angiopoietin 2 (Angpt2), but whether this process is promoted by Angpt2-induced angiogenesis has not been fully elaborated. Therefore, this study explored the angiogenic activities, in reference to CD34 which is a marker of activated ECs and blood vessels, of cultured ECs in vitro and in ischemic damaged cerebral area in mice following Angpt2 administration. Our results demonstrate that Angpt2 administration (100 ng/mL) is neuroprotective by significantly increasing the CD34 expression in in vitro-cultured ECs, reducing the infarct volume and mitigating neuronal loss, as well as enhancing CD34+vascular length andarea. In conclusion, these results indicate that Angpt2 promotes repair and attenuates ischemic injury,and that the mechanism of this is closely associated with angiogenesis in the brain after stroke.

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

Saneron and Henry Ford Health: Cell Therapy Combo Aids Stroke

This might be difficult for your doctor to acquire the day you have a stroke so you better tell your doctor to stock up. 

Saneron and Henry Ford Health: Cell Therapy Combo Aids Stroke 

Researchers at the Henry Ford Health System (Detroit, MI) and colleagues at Saneron CCEL Therapeutics, Inc. of Tampa, Florida, have found that when human umbilical cord blood cells (HUCBCs) were transplanted into test rats modeled with stroke, the addition of Simvastatin to the HUCBCs significantly increased the therapeutic benefit of the HUCBCs.
The study was published in a recent issue of Neuroscience (227:223-231)
According to N. Kuzmin-Nichols, Saneron president and COO, the combination treatment, delivered 24 hours after the test animals were subjected to simulated stroke, showed an interactive effect in improving neurological outcome. When compared with monotherapy, the combination therapy increased densities of key blood vessels, arteries, and smooth muscle cells in vascular walls.
“HUCBCs are a source for blood stem cells, endothelial cell precursors, mensenchymal cell progenitors, and other multipotent and pluripotent stem cells,” said Kuzmin-Nichols. “They offer a promising therapy for stroke. However, when HUCBCs are used alone, and injected via a vascular route for brain repair, success has been limited.”
Because the drug Simvastatin has been demonstrated to be a neurorestorative and neuroprotective agent in ischemic brain injury, the research team hypothesized that the combination of therapeutic doses of Simvastatin and HUCBCs would increase the expression of Angiopoietin-1(Ang-1, a protein with important roles in vascular development and blood vessel growth) and its receptor Tie2 (a cell-surface receptor that binds with Ang-1). Both Ang-1 and Tie2 promote vascular stabilization and artery growth and could enhance blood vessel remodeling (angiogenesis) after stroke, said the researchers.
According to the researchers, HUCBCs contain a “ready supply” of neurotrophic and angiogenic factors that induce neurogenesis (neural cell repair) and angiogenesis (blood vessel growth), both of which are critical to promoting neurological recovery post stroke. While transplanted HUCBCs have been found to selectively migrate to the injured brain, past and recent research has discovered that few transplanted HUCBCs express neural cell characteristics, and few find their way to the ischemic region of the brain.
“Our study using subtherapeutic monotherapy doses did not show significant improvement in either vasculogenesis or functional outcome,” said Dr. Jieli Chen of Henry Ford Hospital and the study corresponding author. “However, the combination of HUCBCs and Simvastatin did show an interactive effect with a significant improvement in neurological outcome. The combination also amplified endogenous angiogenesis and arteriogenesis, and enhanced vascular remodeling.”
Their in vitro experiments showed that combination treatment and Ang-1 significantly increased capillary-like tube formation and arterial cell migration while anti-Ang-1 significantly reduced combination treatment-induced tube formation and artery cell migration.
Dr. Chen noted that combination treatment likely increases the signaling between the brain vasculature and parenchymal cells that facilitate the migration of HUCBCs into the injured cerebral tissue. This signaling may be attributed to the increased expression of stromal derived factor (SDF-1) in brain vascular and parenchymal cells and its receptor (CXCR4) in HUCBCs.
The researchers concluded that their findings “indicate that the combination of sub-therapeutic doses of Simvastatin and HUCBCs increases Ang1/Tie2 and thereby enhances vascular remodeling that contribute to improved functional outcome after stroke.”
“Our results in this preclincial study support further exploration of the use of combination therapies - such as those combining Simvastatin and HUCBCs - for stroke treatment,” said Kuzmin-Nichols.
Funding for the study came from grants from the National Institute on Aging, RO1 AG031811,National Institute of Neurological Disorder and Stroke, PO1 NS23393 and 1R41NS064708, and from the American Heart Association, grant 09GRNT2300151.