Unusual partners aid blood vessel growth

Date:
March 8, 2022
Source:
Medical College of Georgia at Augusta University
Summary:
Insufficient oxygen to an area like the heart or legs, called
hypoxia, is a cue to our bodies to make more blood vessels, and
scientists have found some unusual partners are key to making that
happen. They've found that two receptors on the surface of those
cells come together then dive inside to enable the new growth,
called angiogenesis, scientists report.



FULL STORY ========================================================================== Insufficient oxygen to an area like the heart or legs, called hypoxia,
is a cue to our bodies to make more blood vessels, and scientists have
found some unusual partners are key to making that happen.


==========================================================================
The endothelial cells that line existing blood vessels are essential to
making new blood vessels, and they've found that two receptors on the
surface of those cells come together then dive inside to enable the new
growth, called angiogenesis, the Medical College of Georgia scientists
report in the journal Nature Cell Biology.

As the name implies, vascular endothelial growth factor receptor 2,
or VEGFR2, typically binds to VEGF, a signaling protein that enables
new blood vessel growth, to go inside the cells. CTR1 enables copper,
an essential mineral key to many important body functions, including angiogenesis, to also go inside.

Corresponding authors Dr. Masuko Ushio-Fukai, vascular biologist, and
Dr. Tohru Fukai, vascular biologist and cardiologist, say that in the
face of hypoxia, VEGF is naturally stimulated outside the cell, then
in turn activates NADPH oxidase, a family of enzymes that generate
reactive oxygen species, or ROS - - in this case the good kind that
enables cell signaling.

They've shown for the first time the step that happens next: ROS then
quickly modifies CTR1, which prompts the VEGF receptor and this copper transporter to bind to each other on the cell surface and move inside
the cell so the sustained VEGFR2 signaling that is essential to new
blood vessel development happens.

When they knocked down the copper transporter, angiogenesis was
severely impaired, Fukai says. They've also used the gene editing
ability of CRISPR-Cas9 to make CTR1 unmodifiable and angiogenesis was
again significantly reduced.



==========================================================================
The scientists worked in models of blood vessel development in the highly vascularized retina and in peripheral artery disease in a limb.

While it's long established that VEGF binding to its receptor causes angiogenesis, this is the first evidence of this binding of receptors
for copper and VEGF that appears to be an early and important connection.

Their findings also make CTR1 a logical therapeutic target when more blood vessels are needed in the face of problems like ischemic heart disease,
and potentially when the process becomes destructive in conditions like
cancer and diabetic retinopathy, the scientists in MCG's Vascular Biology Center say.

Ushio-Fukai's lab has shown that treatment of endothelial cells with
VEGF increases ROS levels in those cells. Her lab subsequently showed
that ROS, a byproduct of our oxygen use, is very important for promoting VEGF-induced angiogenesis. Fukai's lab has focused on the impact copper metabolism has on the body, including its transporter CTR1.

Now they've connected the dots between them. "Once ROS is generated,
it modifies CTR1, which changes its function to become a binding partner
for VEGFR2," she says.



==========================================================================
In this scenario at least, CTR1 does not take copper with it when it
moves inside endothelial cells but in other parallel action it still does, which is another boon to angiogenesis.

Once the connections start generating new blood vessels, ROS levels go
down and the CTR1 is free to return to the cell surface where it resumes
its normal job of transporting copper inside, Ushio-Fukai says.

They also have evidence there is always some CTR1 left on the endothelial
cell surface, which can continue to do its usual job of enabling copper
to be used, in this case to also aid angiogenesis.

They also have indications that too much copper can be destructive. The
Fukais have seen copper pile up inside cells in diabetes, where it instead impairs the ability to help make the healthy new blood vessels patients
may need. They say another copper transporter, ATP7A, whose primary job
is regulating copper levels inside cells, is likely a good treatment
target in diabetes, where ATP7A levels are uncharacteristically low.

Copper is an essential trace mineral we need to consume in foods like
nuts and whole grains which also is important to fundamentals like making
red blood cells that carry oxygen. There is a lot of CTR1 in the gut to
enable copper's uptake and use throughout the body.

While VEGF and endothelial cells are both essential to angiogenesis,
it's other cell types, like platelets, immune cells called macrophages
and even tumor cells that make VEGF.

As with copper, physiological levels of ROS are important to body
functions like cell signaling, but high levels produced from unhealthy
habits like smoking and the high-salt Western diet contribute to disease
and conditions like hypertension and atherosclerosis in turn increase ROS.

The research was supported by the National Institutes of Health, the
American Heart Association and the U.S. Department of Veterans Affairs.


========================================================================== Story Source: Materials provided by Medical_College_of_Georgia_at_Augusta_University.

Original written by Toni Baker. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Archita Das, Dipankar Ash, Abdelrahman Y. Fouda, Varadarajan
Sudhahar,
Young-Mee Kim, Yali Hou, Farlyn Z. Hudson, Brian K. Stansfield,
Ruth B.

Caldwell, Malgorzata McMenamin, Rodney Littlejohn, Huabo Su,
Maureen R.

Regan, Bradley J. Merrill, Leslie B. Poole, Jack H. Kaplan, Tohru
Fukai, Masuko Ushio-Fukai. Cysteine oxidation of copper transporter
CTR1 drives VEGFR2 signalling and angiogenesis. Nature Cell Biology,
2022; 24 (1): 35 DOI: 10.1038/s41556-021-00822-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220308102733.htm

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