Endothelial SCUBE2 Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis

We need angiogenesis to help our recovery. What the fuck is your doctor doing to accomodate that?
http://atvb.ahajournals.org/content/37/1/144?etoc=

Yuh-Charn Lin, Tsu-Yi Chao, Chi-Tai Yeh, Steve R. Roffler, Reiji Kannagi, Ruey-Bing Yang

https://doi.org/10.1161/ATVBAHA.116.308546

Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37:144-155

Originally published November 10, 2016

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Abstract

Objective—Vascular endothelial growth factor (VEGF), a major mediator of angiogenesis, exerts its proangiogenic action by binding to VEGFR2 (VEGF receptor 2), the activity of which is further modulated by VEGFR2 coreceptors such as neuropilins. However, whether VEGFR2 is regulated by additional coreceptors is not clear. To investigate whether SCUBE2 (signal peptide-CUB-EGF domain-containing protein 2), a peripheral membrane protein expressed in vascular endothelial cells (ECs) known to bind other signaling receptors, functions as a VEGFR2 coreceptor and to verify the role of SCUBE2 in the VEGF-induced angiogenesis.

Approach and Results—SCUBE2 lentiviral overexpression in human ECs increased and short hairpin RNA knockdown inhibited VEGF-induced EC growth and capillary-like network formation on Matrigel. Like VEGF, endothelial SCUBE2 was upregulated by hypoxia-inducible factor-1α at both mRNA and protein levels. EC-specific Scube2 knockout mice were not defective in vascular development but showed impaired VEGF-induced neovascularization in implanted Matrigel plugs and recovery of blood flow after hind-limb ischemia. Coimmunoprecipitation and ligand-binding assays showed that SCUBE2 forms a complex with VEGF and VEGFR2, thus acting as a coreceptor to facilitate VEGF binding and augment VEGFR2 signal activity. SCUBE2 knockdown or genetic knockout suppressed and its overexpression promoted the VEGF-induced activation of downstream proangiogenic and proliferating signals, including VEGFR2 phosphorylation and mitogen-activated protein kinase or AKT activation.

Conclusions—Endothelial SCUBE2 may be a novel coreceptor for VEGFR2 and potentiate VEGF-induced signaling in adult angiogenesis.

Potential molecular link identified between excess fat in the blood and blood vessel recovery in ischemia

How is your doctor reducing the fat in your blood to get better angiogenesis? 

Potential molecular link identified between excess fat in the blood and blood vessel recovery in ischemia

The buildup of fat in the blood makes a bad situation worse - it not only raises a person's risk for heart attack or stroke but also impairs the growth of new blood vessels. How excess fat in the blood - a condition known as hyperlipidemia - blocks vessel growth was unclear, but new work by researchers at Temple University School of Medicine (TUSM) shows that a molecule known as caspase-1 plays a central role and that preventing its activity could be the key to building new blood vessels and restoring blood supply to oxygen-starved tissues.
"Caspase-1 acts as a lipid sensor in endothelial cells, which are abundant in the inner lumen of blood vessels," explained Xiao-Feng Yang, MD, PhD, FAHA, Professor of Pharmacology, Professor of Microbiology and Immunology in the Center for Metabolic Disease Research, Professor in the Cardiovascular Research Center and Professor in the Sol Sherry Thrombosis Research Center at TUSM, and senior investigator on the new study, which appears in print in the July 10 issue of the Journal of Biological Chemistry. "When lipids reach dangerously high levels in the circulation, the caspase-1-inflammasome complex initiates inflammation in the blood vessel," notes, Dr. Yang. "It turns out that caspase-1 signaling also inhibits endothelial cell growth, undermining the ability of the vasculature to recover from ischemic disease."
Ischemic diseases, which include heart attack, stroke, and peripheral artery disease, are a leading cause of illness and death in the United States. Ischemia starves tissues of blood and oxygen, resulting in severe damage to the blood vessels in affected tissues. Finding ways to therapeutically restore blood flow after ischemia without causing further tissue injury is a major goal in metabolic cardiovascular research.
Caspase-1 inhibition could prove to be hugely important in the treatment of ischemic disease. In their new report, Dr. Yang and colleagues show that the caspase-1 distress signals triggered by hyperlipidemia produce different effects in endothelial cells of differing size. In small endothelial cells, it triggers cell death, but in larger cells, it is involved in endothelial cell activation, in which the inner lining of the blood vessel undergoes a series of changes that ultimately contribute to the high lipid-induced inflammatory response.

"The growth status of endothelial cells is important to the inflammatory process," according to Dr. Yang. The major growth signaling pathway in endothelial cells is mediated by vascular endothelial growth factor receptor-2 (VEGFR-2), which also happens to be necessary for angiogenesis - the formation of new blood vessels.
In a series of experiments in human endothelial cells, Dr. Yang's team-- in collaboration with Hong Wang, MD, PhD, FAHA, EMBA, Associate Dean of Research, Director of the Center for Metabolic Disease Research, Professor of Pharmacology, Professor in the Cardiovascular Research Center and Professor in the Sol Sherry Thrombosis Research Center at TUSM, and Eric T. Choi, MD, Chief of Vascular and Endovascular Surgery at Temple University Hospital, and Associate Professor of Surgery at TUSM-- demonstrated that when caspase-1 was inhibited, VEGFR-2 activity was enhanced and the cells' angiogenic function restored. The cells successfully organized themselves into capillary-like structures in a tube-formation assay designed to measure angiogenic potential.
Similar effects on angiogenesis were seen in caspase-1-deficient mice with hyperlipidemia and hind-limb ischemia. Compared to hyperlipidemic mice with normal caspase-1 expression, mice lacking the sensor molecule had better blood flow and vessel growth in their ischemic limb.
"The findings describe the significance of the caspase-1 pathway to post-ischemia revascularization," Dr. Yang said. "From a therapeutic point of view, we want to try to trigger revascularization and make existing vessels recover as soon as possible. The novel caspase-1 signaling pathway could have therapeutic potential in this area."
Dr. Yang next intends to figure out how caspase-1 modulates the activities of endothelial cells and of bone marrow-derived stem cells, which function in vascular repair. In research published earlier in 2015, he and colleagues discovered that caspase-1 activation weakened the vascular repair activity of stem cells in hyperlipidemic mice. Those findings could have implications for stem cell-based therapies for ischemia.

Source:

Temple University Health System

VEGFR1 and VEGFR2 Involvement in Extracellular Galectin-1- and Galectin-3-Induced Angiogenesis

We need angiogenesis to supply blood to any migrating stem cells or migratory neurogenesis. Ask your doctor to translate and put into a useful stroke protocol. Unless you ask, nothing is going to get done.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0067029

Abstract

Aim

Accumulating evidence suggests that extracellular galectin-1 and galectin-3 promote angiogenesis. Increased expression of galectin-1 and/or galectin-3 has been reported to be associated with tumour progression. Thus, it is critical to identify their influence on angiogenesis.

Methods

We examined the individual and combined effects of galectin-1 and galectin-3 on endothelial cell (EC) growth and tube formation using two EC lines, EA.hy926 and HUVEC. The activation of vascular endothelial growth factor receptors (VEGFR1 and VEGFR2) was determined by ELISA and Western blots. We evaluated the VEGFR1 and VEGFR2 levels in endosomes by proximity ligation assay.

Results

We observed different responses to exogenous galectins depending on the EC line. An enhanced effect on EA.hy926 cell growth and tube formation was observed when both galectins were added together. Focusing on this enhanced effect, we observed that together galectins induced the phosphorylation of both VEGFR1 and VEGFR2, whereas galectin-1 and −3 alone induced VEGFR2 phosphorylation only. In the same way, the addition of a blocking VEGFR1 antibody completely abolished the increase in tube formation induced by the combined addition of both galectins. In contrast, the addition of a blocking VEGFR2 antibody only partially inhibited this effect. Finally, the addition of both galectins induced a decrease in the VEGFR1 and VEGFR2 endocytic pools, with a significantly enhanced effect on the VEGFR1 endocytic pool. These results suggest that the combined action of galectin-1 and galectin-3 has an enhanced effect on angiogenesis via VEGFR1 activation, which could be related to a decrease in receptor endocytosis.

Membrane Trafficking and Endothelial-Cell Dynamics During Angiogenesis

Only 28 pages and I learned something new, vasculogenesis vs angiogenesis, I wonder which is more applicable for us survivors that have lots of dead area. Cool diagrams in the pdf, sections listed, details at the link.

http://cdn.intechweb.org/pdfs/31164.pdf
1. Introduction
The formation of new blood vessels, or neovascularization, involves multiple processes,
including cell proliferation and migration, cell-cell and cell-matrix adhesion, and tube
morphogenesis. Neovascularization can occur through one of two events: vasculogenesis,
the de novo formation of blood vessels from angioblasts; or angiogenesis, the extension of
new vessels from a pre-existing vasculature. Among these, angiogenesis in particular is
relevant throughout life; its dysregulation has been causally related to several disorders that
involve malignancy, inflammation, and ischemia. Angiogenesis is thought to depend on a
set of signaling proteins – including certain kinases, integrins and vascular endothelial
growth factor receptor-2 (VEGFR2) – that are enriched in specific plasma membrane
domains. Both physiological and pathological angiogenesis rely on intracellular trafficking,
a process that governs signaling by such proteins, as well as cell motility.
In this chapter, we discuss our current understanding of angiogenesis from the perspective
of trafficking of the membrane components that are responsible for endothelial-cell (EC) dynamics.
2. Angiogenesis: Mechanism and importance

Fig. 1. Schematic representation of a mature blood vessel. Endothelial cells at the luminal
side line tubular blood vessel. The smooth muscle cells and the pericytes that remain in
contact with the endothelial cell lining through the basement membrane strengthen this
tubular structure.
2.1 Vasculogenesis
2.2 Angiogenesis
2.3 Pathological angiogenesis
3. Ligands and receptors in angiogenesis
3.1 The VEGF-VEGFR system coordinates the process of angiogenesis
3.1.1 VEGF
3.2 VEGF receptors
3.2.1 VEGFR1
3.2.2 VEGFR2
3.2.3 VEGFR3
3.2.4 Neuropilins (NRP)
3.3 Role of the extracellular matrix (ECM) in endothelial-cell interactions during angiogenesis
3.4 Role of Integrin in endothelial-cell dynamics during angiogenesis
4. Membrane trafficking
4.1 Biosynthetic/secretory pathway
4.2 Endocytic and exocytic pathways
4.3 Endocytic trafficking of VEGFR2
4.4 Secretory transport of VEGFR2
4.5 VEGFR2 trafficking and angiogenesis