Rebuild shredded blood vessels
Medical College of Georgia at Augusta University
Angiogenesis
is the ability to form new blood vessels, and diabetes not only damages
existing blood vessels, it hinders this innate ability to grow new ones in the
face of disease and injury, say experts at the Vascular Biology Center at the
Medical College of Georgia.
Endothelial
cells line our blood vessels and are essential to that new blood vessel growth.
Now
the MCG scientists have the first evidence that in the face of diabetes, even
one 45-minute session of moderate intensity exercise enables more exosomes,
submicroscopic packages filled with biologically active cargo, to deliver
directly to those cells more of the protein, ATP7A, which can set angiogenesis
in motion, they report in The FASEB Journal.
Not unlike the most sophisticated and efficient delivery services we have all come to rely upon, particularly during the pandemic, what exosomes carry depends on where they come from and where they are headed, says Dr. Tohru Fukai, MCG vascular biologist and cardiologist.
While
he and co-corresponding author MCG vascular biologist Dr. Masuko Ushio-Fukai
are not yet certain of the origin of these helpful exosomes, it's clear that
one place they deliver is to endothelial cells, Fukai says.
In
both an animal model of type 2 diabetes and a handful of healthy
50-something-year-olds, two weeks of volunteer running on a wheel for the mice
and that one cardio session for the humans increased levels of ATP7A in the
exosomes that attached to endothelial cells.
At
that point, the activity did not significantly impact the weight of the mice,
the scientists note, but it did also increase a marker of endothelial function
and factors like, vascular endothelial growth factor, needed for angiogenesis.
Exercise
also increased the amount of the powerful, natural antioxidant extracellular
superoxide dismutase, or SOD3, but it's the heavier payload of ATP7A, which is
also known to deliver the essential mineral copper to cells, that is key to
making good use of the SOD3 present, Ushio-Fukai says.
SOD3,
is an important natural antioxidant produced by vascular smooth muscle cells in
the walls of blood vessels as well as skeletal muscle cells, which helps us
maintain healthy levels of reactive oxygen species, or ROS. ROS is a natural
byproduct of our use of oxygen that is an important cell signal, enabling a
variety of functions. But in diabetes, high blood sugar levels result in high
ROS levels that instead hinder important normal functions.
The
Fukais have shown that ATP7A levels are reduced in diabetes. They also now have
some of the first evidence that exosomes circulating in the plasma of sedentary
animal models of type 2 diabetes actually impair angiogenesis when placed in a
dish with human endothelial cells, as well as in an animal model of wound
healing.
The
scientists suggest that synthetic exosomes, already under study as
drug-delivery mechanisms, could one day work as an "exercise mimetic"
to improve patients' ability to grow new blood vessels when diabetes has
damaged their innate ability.
In
fact, they have already generated exosomes in which SOD3 is overexpressed and
found improved angiogenesis and healing in a mouse model of diabetes.
The
way it's supposed to work is SOD3 is naturally silenced in endothelial cells,
so they must get it from other cells, notes Ushio-Fukai, hence the importance
of exosome delivery. SOD3 must then bind to endothelial cells at its natural
spot called the heparin-binding domain, and the copper transporter ATP7A must
be present to enable SOD3 to be active there, Fukai says. Both ATP7A and the
binding site are key, Fukai notes. For example, when they removed the binding
site from the endothelial cells, which can happen in nature, the benefits were
lost.
Once
on the scene and active, SOD3 converts the ROS superoxide into hydrogen
peroxide, or H2O2, another signaling ROS that helps support normal endothelial
cell function. The Fukais have reported that in human endothelial cells,
overexpressing SOD3 promotes angiogenesis by increasing H2O2.
A
copper connection also runs throughout this process as endothelial cells
regularly use a lot of copper, and ATP7A, known to transport the essential
mineral that we consume in foods like nuts and whole grains, is dependent on
copper itself.
Physical
exercise, like running or walking on treadmill, prompts muscles to contract
which in turn prompts release of exosomes into the blood.
When
Fukai was a postdoc in the Emory University Section of Cardiology he was part
of the research group that was the first to show that exercise increases SOD3
activity. SOD3 levels decrease with age and with some disease states like
diabetes and hypertension.
Exosomes
are being studied as biomarkers for a wide range of diseases like cancer and
diabetes as well as precise treatment delivery tools. For example, exosomes
produced by a cancer cell will hone right back to a cancer cell.
About
1 in 10 Americans have diabetes, according to the Centers for Disease Control
and Prevention.
Story
Source:
Materials provided by Medical College of Georgia at Augusta
University. Original writt
