..effect of VEGF gene inactivation ... on muscle enzyme activity, capillary supply & endurance exercise, 2020, Breen et al

Andy · Sep 17, 2020

Full title: Synergistic effect of VEGF gene inactivation in endothelial cells and skeletal myofibers on muscle enzyme activity, capillary supply and endurance exercise in mice

As it says, in mice.

New Findings

1. What is the central question of this study?

Dose VEGF expressed by both endothelial cells and skeletal myofibers maintain the number of skeletal muscle capillaries and regulate endurance exercise.

2. What is the main finding and its importance?

VEGF expressed by both endothelial cells and skeletal myofibers is not essential for maintaining capillary number but does contribute to exercise performance.

Abstract
Many chronic diseases lead to exercise intolerance, with loss of skeletal muscle capillaries. While many muscle cell types (myofibers, satellite cells, endothelial cells, macrophages and fibroblasts) express VEGF, most muscle VEGF is stored in myofibers vesicles which can release VEGF to signal VEGF receptor‐expressing cells. VEGF gene ablation in myofibers or endothelial cells alone does not cause capillary regression.

We hypothesized that simultaneously deleting endothelial cell (EC) and skeletal myofiber (Skm) VEGF would cause capillary regression and impair exercise performance. This was tested in adult mice by simultaneous conditional deletion of the VEGF gene (Skm/EC‐VEGF‐/‐ mice) through the use of VEGFLoxP, HSA‐Cre‐ERT2 and PDGFb‐iCre‐ERT2 transgenes. These double‐deletion mice were compared to three control groups – WT, EC VEGF deletion alone and myofiber VEGF deletion alone.

Three weeks after initiating gene deletion, Skm/EC‐VEGF‐/‐ mice, but not SkmVEGF‐/‐ or EC‐VEGF‐/‐ mice, reached exhaustion 40 minutes sooner than WT mice in treadmill tests (p = 0.002). WT, SkmVEGF‐/‐, and EC‐VEGF‐/‐, but not Skm/EC‐VEGF‐/‐ mice, gained weight over the three weeks. Capillary density, fiber area and capillary:fiber ratio in soleus, plantaris, gastrocnemius and cardiac papillary muscle were similar across the groups. Phosphofructokinase and pyruvate dehydrogenase activities increased only in Skm/EC‐VEGF‐/‐ mice.

These data suggest that deletion of VEGF signaling simultaneously in endothelial cells and myofibers, while reducing treadmill endurance and despite compensatory augmentation of glycolysis, is not required for muscle capillary maintenance. Reduced endurance remains unexplained, but may possibly be related to a role for VEGF in controlling perfusion of contracting muscle.
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Paywall, https://physoc.onlinelibrary.wiley.com/doi/10.1113/EP088924
Sci hub, https://sci-hub.tw/10.1113/EP088924

Andy · Sep 17, 2020

May be of interest to us.

Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome

We observed highly significant reductions in the concentration of circulating interleukin (IL)-16, IL-7, and Vascular Endothelial Growth Factor A (VEGF-A) in ME/CFS patients.
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Open access, https://www.sciencedirect.com/science/article/pii/S1043466615301071

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome

Post hoc t-tests revealed prominent decreases in the levels of many pro- and anti-inflammatory cytokines in ME/CFS as compared with ND controls, including IL1ra, IL1β, IL5, IL6, IL8, IL10, IL12p40, IL17F, TNFβ, SCF (SF), CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF), PDGFBB, FGFb, VEGFA, LIF, resistin, serpin E1 (PAI1), sICAM1 (CD54) and VCAM1 (CD106).
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Sci hub, https://sci-hub.tw/https://www.nature.com/articles/mp201529

duncan · Sep 17, 2020

Are they looking at a relevant marker but for the wrong reasons, I wonder...:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC300888/

Snow Leopard · Sep 17, 2020

Besides the ethical issues, the results of this study are interesting.

It reminds me of another study on VEGF and endurance I likely had open on a tab, but never got around to reading (and lost on a reboot).

I was looking at ways that viruses could cause dysregulation (and feedback loops) of VEGF signalling and looking at exacerbation due to exercise, with kinetics similar to the time frame of PEM.

This was part of my interest in Integrins, Neuropilins in the thread I started a while back. (and also plexins, and the ligands of all 3 - semaphorins)

https://www.sciencedirect.com/science/article/pii/S1097276505000766
https://link.springer.com/article/10.1007/s10456-008-9097-1
https://www.sciencedirect.com/science/article/abs/pii/S1050173801001402

And a focus on mechanosensing in endothelial cells:
https://link.springer.com/article/10.1007/s11427-014-4705-3
https://pubmed.ncbi.nlm.nih.gov/32025034/

We (or at least I) still don't know enough about this to put together a highly specific hypothesis however.

duncan · Sep 17, 2020

Snow Leopard said: ↑

I was looking at ways that viruses could cause dysregulation (and feedback loops) of VEGF signalling and looking at exacerbation due to exercise, with kinetics similar to the time frame of PEM.
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I thought a general rule of thumb is pathogens resulted in elevated VEGF, at least as far as serum VEGF (vs CSF VEGF as pertains to one of the first two studies in this thread, not the one I linked to.) Same with cancerous tumors. Low VEGF seemed peculiar to a couple cardiac issues, and a host of neuro-degenerative diseases.

Snow Leopard · Sep 18, 2020

duncan said: ↑

I thought a general rule of thumb is pathogens resulted in elevated VEGF, at least as far as serum VEGF (vs CSF VEGF as pertains to one of the first two studies in this thread, not the one I linked to.) Same with cancerous tumors. Low VEGF seemed peculiar to a couple cardiac issues, and a host of neuro-degenerative diseases.
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Yes, that's why I'm interested in the receptor function, not merely VEGF levels. Also consider what happens to VEGF expression once the virus is eliminated...

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..effect of VEGF gene inactivation ... on muscle enzyme activity, capillary supply & endurance exercise, 2020, Breen et al

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