For those who wanted to dig a bit deeper into the new research announced today...Here's a recap:
Dr. Frédéric Charron, researcher at the Institut de recherches cliniques de Montréal (IRCM), and his team have shown for the first time that a key molecule of the vascular system directs axons during the formation of neural circuits. This connection between the nervous system and the vascular system could be a good starting point for the development of therapies for neurodegenerative diseases. The discovery will be published June 9 by Neuron.
A key molecule of the vascular system called vascular endothelial growth factor (VEGF) directs axons during the formation of neural circuits, researchers at the Institut de recherches cliniques de Montréal (IRCM) have found.
The researchers used a microscopic device to control and observe, in real time, the axon’s behavior in response to guidance molecules. This technique allowed the researchers to follow the axon’s trajectory and revealed the VEGF’s (vascular endothelial growth factor) role in directing axons.
They identified Flk-1 as the receptor responsible for this effect, making it a prime target for the development of therapies to re-grow axons after lesions of the central nervous system or neurodegenerative diseases.
This could have an important long-term impact in the field of spinal cord repair as well as the treatment of neurodegenerative diseases, the researchers said.
http://www.kurzweilai.net/re-growing-axons-after-lesions-of-the-central-nervous-system
http://www.sciencedaily.com/releases/2011/06/110608131330.htm
What does this mean? What did Dr. Charron discover?? How could Flk-1 help re-grow axons and repair lesions in the CNS?? Well, I looked up the abstract for the paper being published in Neuron, did some more research and found out some interesting things---
and it's all about the endothelium ---nitric oxide, VEGF and Flk-1. The specific research is on embryonic development---but the connection continues for our adult lives.
For those who do not know about the endothelium, the lining of our blood vessels, and CCSVI and MS, I suggest you start at the very beginning, and read the Endothelial Health Program. I created it for Jeff, but put it online for everyone. It's just plain good living....with science to back it up :-) It's based on the work of real doctors, like Dr. John Cooke of Stanford and his book, The Cardiovascular Cure.
http://www.ccsvi.org/index.php/helping-myself/endothelial-health
Now, here's the abstract of the paper from Neuron with the new Canadian research. Very technical, but we'll break it down and get a better understanding of the science.
1. VEGF (vascular endothelial growth factor) is secreted by the floor plate--
(Definition: The floor plate is a structure integral to the developing nervous system of vertebrate organisms. Located on the ventral midline of the embryonic neural tube, the floor plate is a specialized glial structure that spans the anteroposterior axis from the midbrain to the tail regions)
2. Haplodeficiency of Vegf in the floor plate causes axon guidance defects in vivo
3. Inactivation of Flk1 in commissural neurons causes axon guidance defects in vivo
4. VEGF/Flk1 activates Src family kinases and induces commissural axon turning in vitro
Summary
Growing axons are guided to their targets by attractive and repulsive cues. In the developing spinal cord, Netrin-1 and Shh guide commissural axons toward the midline. However, the combined inhibition of their activity in commissural axon turning assays does not completely abrogate turning toward floor plate tissue, suggesting that additional guidance cues are present. Here we show that the prototypic angiogenic factor VEGF is secreted by the floor plate and is a chemoattractant for commissural axons in vitro and in vivo. Inactivation of Vegf in the floor plate or of its receptor Flk1 in commissural neurons causes axon guidance defects, whereas Flk1 blockade inhibits turning of axons to VEGF in vitro. Similar to Shh and Netrin-1, VEGF-mediated commissural axon guidance requires the activity of Src family kinases. Our results identify VEGF and Flk1 as a novel ligand/receptor pair controlling commissural axon guidance.
http://www.cell.com/neuron/abstract/S0896-6273(11)00343-6
OK....Flk-1 is the important element in this equation. And these researchers believe this pathway will regrow axons after damage. When we are forming in utero, Flk-1 is part of the formation of our neuronal and vascular systems. If it is blocked or inactivated, the axons in our brains will not be able to form healthy neuronal pathways. And now it appears, Flk-1 can help heal axons. So, what is this Flk-1???
Flk-1 is a protein and one of two vascular endothelial growth factors. It is needed to form our blood vessels and our neuronal pathways.....
Flk-1 (human counterpart, KDR) tyrosine kinase, which is one of the two VEGF receptors, is crucial for vascular development. Recently, we showed that, among tyrosine residues of KDR, tyrosine residues 1175 (Y1175, corresponding to Y1173 in murine Flk-1) and Y1214 (Y1212 in Flk-1) are autophosphorylated in response to VEGF, and that Y1175 is important for VEGF-dependent phospholipase C?/PKC/mitogen-activated protein kinase activation leading to DNA synthesis in cultured endothelial cells. However, the importance of these tyrosine residues in Flk-1/KDR in vivo is not yet known. To examine the role of these Flk-1 tyrosine residues in vivo, we generated knock-in mice substituting Y1173 and Y1212 of the Flk-1 gene with phenylalanine, respectively. As a result, Flk-11173F homozygous mice died between embryonic days 8.5 and 9.5 without any organized blood vessels or yolk sac blood islands, and hematopoietic progenitors were severely reduced, similar to the case of Flk-1 null mice. In contrast, Flk-11212F homozygous mice were viable and fertile. These results suggest that the signaling via Y1173 of Flk-1 is essential for endothelial and hematopoietic development during embryogenesis.
http://www.cell.com/neuron/abstract/S0896-6273(11)00343-6
So, let's connect all of the dots. Flk-1 is shown to be important in forming neuronal connections and axons in utero. This is from new research released today. How is this connected to CCSVI? How does this affect us once we are out of the womb, and as our bodies mature?
It's all about blood flow. Open vessels, shear stress, nitric oxide release, vasodilation and a healthy endothelium allow for Flk-1 mediated activity as we age.
If you're still with me, here is more research on the connection....as we age and our endothelial function decreases, it is even more important to live a vessel-healthy life! Flk-1 remains important in our bodies' signaling---
The primary finding of this investigation is that impairment of Flk-1-mediated PI3-kinase/Akt signaling contributes to the age-induced reduction of flow-dependent, NO-mediated vasodilation in coronary arterioles from male Fischer-344 rats. This finding confirms earlier observations of reduced NO-mediated vasodilation in coronary resistance arteries of middle-aged rats (6) and provides novel insight into the effects of aging on cellular signaling mechanisms that activate eNOS in coronary arterioles. Our current findings indicate that age-related decrements in several components of the Flk-1 PI3-kinase/Akt signaling pathway contribute to the loss of flow- and VEGF-induced vasodilation that occurs with age in coronary arterioles. In contrast, ACh-induced signaling through G protein-coupled receptors is maintained with age, suggesting that Flk-1-mediated signaling is a critical target in age-induced coronary endothelial dysfunction.
Shear stress is a potent physiological stimulus for release of NO and is dependent on an intact endothelium (22). Flow-induced vasodilation is a key mediator of local vascular control in the coronary circulation (34, 35) and is critically dependent on endothelium-dependent release of NO, as evidenced by reports demonstrating that nitric oxide synthase inhibition eliminates flow-induced vasodilation in coronary arterioles of several species (25, 30, 41). Recent studies have indicated that VEGFR2, also known as Flk-1 (4), is rapidly tyrosine phosphorylated by flow (18, 24) and VEGF (14), leading to PI3-kinase-Akt-eNOS activation. Our results show that flow- and VEGF-induced vasodilatory responses of coronary arterioles are dramatically reduced by inhibition of Flk-1 with SU-1498. Importantly, our current results show that exposure to flow increases phosphorylation of Flk-1 in coronary arterioles from young rats, but not in coronary arterioles from old rats. Thus our results indicate that flow-induced vasodilation is impaired in coronary arterioles of senescent rats (24 mo) and extend previous findings in vessels from cardiac (6) and skeletal (29, 42) muscle by demonstrating that deficits in Flk-1/PI3-kinase/Akt signaling contribute to age-related reductions of NO-mediated vasodilation in coronary arterioles. Our current work also indicates that the decrease in Flk-1 activation that occurs with age is accompanied by a decrease in Flk-1 protein levels.
http://ajpheart.physiology.org/content/295/6/H2280.full
The bottom line-----Endothelial health is most likely essential for the axonal system, as well as the vascular health. Further research will hopefully define the connection between neuronal health, the endothelium and Flk-1 in vivo. And maybe healing axonal damage in the CNS!
Our body is one. Let's get these doctors talking to each other!!!
Here's the Endothelial Health program once again.
http://www.ccsvi.org/index.php/helping-myself/endothelial-health
take care, and as the Hubbards say, "Go with the Flow!!"
Joan