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Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature.

Publication ,  Journal Article
Vakili, S; Izydore, EK; Losert, L; Cabral, WA; Tavarez, UL; Shores, K; Xue, H; Erdos, MR; Truskey, GA; Collins, FS; Cao, K
Published in: Aging cell
October 2024

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder in children caused by a point mutation in the lamin A gene, resulting in a toxic form of lamin A called progerin. Accelerated atherosclerosis leading to heart attack and stroke are the major causes of death in these patients. Endothelial cell (EC) dysfunction contributes to the pathogenesis of HGPS related cardiovascular diseases (CVD). Endothelial cell-cell communications are important in the development of the vasculature, and their disruptions contribute to cardiovascular pathology. However, it is unclear how progerin interferes with such communications that lead to vascular dysfunction. An antibody array screening of healthy and HGPS patient EC secretomes identified Angiopoietin-2 (Ang2) as a down-regulated signaling molecule in HGPS ECs. A similar down-regulation of Ang2 mRNA and protein was detected in the aortas from an HGPS mouse model. Addition of Ang2 to HGPS ECs rescues vasculogenesis, normalizes endothelial cell migration and gene expression, and restores nitric oxide bioavailability through eNOS activation. Furthermore, Ang2 addition reverses unfavorable paracrine effects of HGPS ECs on vascular smooth muscle cells. Lastly, by utilizing adenine base editor (ABE)-corrected HGPS ECs and progerin-expressing HUVECs, we demonstrated a negative correlation between progerin and Ang2 expression. Lastly, our results indicated that Ang2 exerts its beneficial effect in ECs through Tie2 receptor binding, activating an Akt-mediated pathway. Together, these results provide molecular insights into EC dysfunction in HGPS and suggest that Ang2 treatment has potential therapeutic effects in HGPS-related CVD.

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Published In

Aging cell

DOI

EISSN

1474-9726

ISSN

1474-9718

Publication Date

October 2024

Start / End Page

e14375

Related Subject Headings

  • Developmental Biology
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
  • 11 Medical and Health Sciences
  • 06 Biological Sciences
 

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Vakili, S., Izydore, E. K., Losert, L., Cabral, W. A., Tavarez, U. L., Shores, K., … Cao, K. (2024). Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature. Aging Cell, e14375. https://doi.org/10.1111/acel.14375
Vakili, Sahar, Elizabeth K. Izydore, Leonhard Losert, Wayne A. Cabral, Urraca L. Tavarez, Kevin Shores, Huijing Xue, et al. “Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature.Aging Cell, October 2024, e14375. https://doi.org/10.1111/acel.14375.
Vakili S, Izydore EK, Losert L, Cabral WA, Tavarez UL, Shores K, et al. Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature. Aging cell. 2024 Oct;e14375.
Vakili, Sahar, et al. “Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature.Aging Cell, Oct. 2024, p. e14375. Epmc, doi:10.1111/acel.14375.
Vakili S, Izydore EK, Losert L, Cabral WA, Tavarez UL, Shores K, Xue H, Erdos MR, Truskey GA, Collins FS, Cao K. Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature. Aging cell. 2024 Oct;e14375.
Journal cover image

Published In

Aging cell

DOI

EISSN

1474-9726

ISSN

1474-9718

Publication Date

October 2024

Start / End Page

e14375

Related Subject Headings

  • Developmental Biology
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
  • 11 Medical and Health Sciences
  • 06 Biological Sciences