Nature 451, 1008-1012 (21 February 2008) | doi:10.1038/nature06613; Received 15 October 2007; Accepted 20 December 2007
HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha
...Anyone want to try a synopsis? I'll write mine after 3 days. ...
No, but I Look forward to yours. Here are some related comments on it and my observations (I undestand this is research only - but I like to think ahead to the possible therapeutic application of what is learned, so my comments lean that way. Note the alpha after PGC-1 did not post):
“…PGC-1 and ERR- , major regulators of mitochondrial function in response to exercise and other stimuli, also control a novel angiogenic pathway that delivers needed oxygen and substrates. PGC-1 may provide a novel therapeutic target for treating ischaemic diseases. …”
Seems to me like a “side effect” of any therapy suppressing PGC-1 would be feeling quite weak, if the mitochondria are not working well. – Would not want my heart muscle to get tired and stop.
“PGC-1 is known to co-activate several transcription factors, including many members of the MEF2 (myocyte enhancer factor-2), FOXO (forkhead transcription factor O) and nuclear receptor families2. …Thus, PGC-1 seems to stimulate VEGF expression at least in part by the coactivation of ERR- . …”
Seems to me like PGC-1 plays a very fundamental and complex role in many parts of bio chemistry – so complex that medical science should not even consider “therapeutic manipulation" of it in humans.
I not opposed to some in vivo mouse etc studies to better understand this role. But as I like to observe: “My body is smarter than all the doctors put together.”
“… The regulation of VEGF in response to hypoxia is thought to be mediated primarily through the
well-known HIF factors. Surprisingly, the novel PGC-1 /ERR- pathway described here is apparently independent of the HIF pathway. …”
Bold not “well-known” by me – can anyone comment? At least expand “HIF.” I am especially interested in knowing if there are some specific surface sites that function in the HIF process of stimulation of new vascularization.
“…Angiogenesis is also crucial to tumour progression and metastasis. The interface of metabolism with cancer progression has been the subject of renewed scrutiny in recent years18. //// {Genetech's "Avastin" is now billion dollar market drug hitting VEGF} //// It will be of great interest to elucidate the role of PGC-1 and ERR- in this interface, given the important function of these molecules in metabolic control.
Human clinical trials that examine the efficacy of VEGF delivery as therapy in various settings, including chronic limb ischaemia, have yielded disappointing results6, 19, 20. In large part this may be because the use of VEGF alone seems to lead to immature, leaky vessels19. The generation of fully functional vessels requires the coordinated action of numerous signals, such as PDGF-BB and the angiopoetins6. One therapeutic approach to this problem may be to modulate a transcriptional regulator that coordinates these signals appropriately6, 21. The PGC-1 /ERR- pathway provides such an opportunity. …”
Again, I like working with nature –not trying to manipulate it. I don’t know if they can avoid going bankrupt, but IMHO
www.aastrom.com has the preferred approach for chronic limb ischaemia and related problems, even in the heart and bones.
I also like:
www.peregrine.com ideas, now in P2 trials of bavituximab, for starving ALL of the tumor, not just of the new blood vessels needed for tumor growth by hitting VEGF, but even destroying the ones the tumor already has. Thus, selectively killing the whole tumor!
Bavituximab is a monoclonal antibody, which targets phosphatidylserine molecules [PS] presented on the outer side of cancer blood vessel cells. PS is only a side-effect, a characteristic of cancerous tissues from which cancer does not benefit. In normal, healthy vascular cells, PS is tightly segregated to the internal side of the cell. This segregation appears to be impaired in many kinds of tumor blood vessels, where PS becomes present on the external side of the cells. This phenomenon was observed in lung, breast, prostate and pancreatic cancer, among others. Monoclonal antibodies that are injected into the blood stream can recognize only targets that are presented on the external side of cells, healthy cells that have PS exclusively on their inner side will be unaffected, while cancer blood vessels would be targeted by the antibody exclusively.
Can anyone give summary of paper’s ref 9 (Nature paper from 2003)?
