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Contraction of human brain vascular pericytes in response to islet amyloid polypeptide is reversed by pramlintide

Nuñez-Diaz, Cristina LU ; Pocevičiūtė, Dovilė LU orcid ; Schultz, Nina LU ; Welinder, Charlotte LU ; Swärd, Karl LU and Wennström, Malin LU (2023) In Molecular Brain 16(1).
Abstract

The islet amyloid polypeptide (IAPP), a pancreas-produced peptide, has beneficial functions in its monomeric form. However, IAPP aggregates, related to type 2 diabetes mellitus (T2DM), are toxic not only for the pancreas, but also for the brain. In the latter, IAPP is often found in vessels, where it is highly toxic for pericytes, mural cells that have contractile properties and regulate capillary blood flow. In the current study, we use a microvasculature model, where human brain vascular pericytes (HBVP) are co-cultured together with human cerebral microvascular endothelial cells, to demonstrate that IAPP oligomers (oIAPP) alter the morphology and contractility of HBVP. Contraction and relaxation of HBVP was verified using the... (More)

The islet amyloid polypeptide (IAPP), a pancreas-produced peptide, has beneficial functions in its monomeric form. However, IAPP aggregates, related to type 2 diabetes mellitus (T2DM), are toxic not only for the pancreas, but also for the brain. In the latter, IAPP is often found in vessels, where it is highly toxic for pericytes, mural cells that have contractile properties and regulate capillary blood flow. In the current study, we use a microvasculature model, where human brain vascular pericytes (HBVP) are co-cultured together with human cerebral microvascular endothelial cells, to demonstrate that IAPP oligomers (oIAPP) alter the morphology and contractility of HBVP. Contraction and relaxation of HBVP was verified using the vasoconstrictor sphingosine-1-phosphate (S1P) and vasodilator Y27632, where the former increased, and the latter decreased, the number of HBVP with round morphology. Increased number of round HBVP was also seen after oIAPP stimulation, and the effect was reverted by the IAPP analogue pramlintide, Y27632, and the myosin inhibitor blebbistatin. Inhibition of the IAPP receptor with the antagonist AC187 only reverted IAPP effects partially. Finally, we demonstrate by immunostaining of human brain tissue against laminin that individuals with high amount of brain IAPP levels show significantly lower capillary diameter and altered mural cell morphology compared to individuals with low brain IAPP levels. These results indicate that HBVP, in an in vitro model of microvasculature, respond morphologically to vasoconstrictors, dilators, and myosin inhibitors. They also suggest that oIAPP induces contraction of these mural cells and that pramlintide can reverse such contraction.

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author
; ; ; ; and
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Amylin, Blood flow, Diabetes, Mural cells, Vasculopathy
in
Molecular Brain
volume
16
issue
1
article number
25
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85148114655
  • pmid:36793056
ISSN
1756-6606
DOI
10.1186/s13041-023-01013-1
language
English
LU publication?
yes
id
a8ce8253-68f0-46ac-b621-c39a578a488c
date added to LUP
2023-03-03 12:13:02
date last changed
2024-06-14 00:24:08
@article{a8ce8253-68f0-46ac-b621-c39a578a488c,
  abstract     = {{<p>The islet amyloid polypeptide (IAPP), a pancreas-produced peptide, has beneficial functions in its monomeric form. However, IAPP aggregates, related to type 2 diabetes mellitus (T2DM), are toxic not only for the pancreas, but also for the brain. In the latter, IAPP is often found in vessels, where it is highly toxic for pericytes, mural cells that have contractile properties and regulate capillary blood flow. In the current study, we use a microvasculature model, where human brain vascular pericytes (HBVP) are co-cultured together with human cerebral microvascular endothelial cells, to demonstrate that IAPP oligomers (oIAPP) alter the morphology and contractility of HBVP. Contraction and relaxation of HBVP was verified using the vasoconstrictor sphingosine-1-phosphate (S1P) and vasodilator Y27632, where the former increased, and the latter decreased, the number of HBVP with round morphology. Increased number of round HBVP was also seen after oIAPP stimulation, and the effect was reverted by the IAPP analogue pramlintide, Y27632, and the myosin inhibitor blebbistatin. Inhibition of the IAPP receptor with the antagonist AC187 only reverted IAPP effects partially. Finally, we demonstrate by immunostaining of human brain tissue against laminin that individuals with high amount of brain IAPP levels show significantly lower capillary diameter and altered mural cell morphology compared to individuals with low brain IAPP levels. These results indicate that HBVP, in an in vitro model of microvasculature, respond morphologically to vasoconstrictors, dilators, and myosin inhibitors. They also suggest that oIAPP induces contraction of these mural cells and that pramlintide can reverse such contraction.</p>}},
  author       = {{Nuñez-Diaz, Cristina and Pocevičiūtė, Dovilė and Schultz, Nina and Welinder, Charlotte and Swärd, Karl and Wennström, Malin}},
  issn         = {{1756-6606}},
  keywords     = {{Amylin; Blood flow; Diabetes; Mural cells; Vasculopathy}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Molecular Brain}},
  title        = {{Contraction of human brain vascular pericytes in response to islet amyloid polypeptide is reversed by pramlintide}},
  url          = {{http://dx.doi.org/10.1186/s13041-023-01013-1}},
  doi          = {{10.1186/s13041-023-01013-1}},
  volume       = {{16}},
  year         = {{2023}},
}