Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature
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Published on: March 10, 2020
Sahar Vakili1, Elizabeth K Izydore1, Leonhard Losert1
1Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
Insights
Hutchinson-Gilford progeria syndrome (HGPS) involves toxic progerin protein, causing endothelial cell dysfunction and cardiovascular disease. Angiopoietin-2 (Ang2) levels are reduced in HGPS, and restoring Ang2 shows therapeutic potential for HGPS cardiovascular complications.
Area of Science:
- Cardiovascular Biology
- Genetics
- Cell Biology
Background:
- Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature aging.
- Cardiovascular diseases (CVD), including atherosclerosis, heart attack, and stroke, are the primary cause of mortality in HGPS patients.
- Endothelial cell (EC) dysfunction is a key factor in the pathogenesis of HGPS-related CVD, but the underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the role of progerin in endothelial cell dysfunction and communication disruptions in HGPS.
- To identify molecular factors involved in HGPS-related vascular pathology.
- To explore the therapeutic potential of Angiopoietin-2 (Ang2) in mitigating HGPS-associated cardiovascular complications.
Main Methods:
- Antibody array screening of healthy and HGPS patient endothelial cell secretomes.
- Analysis of Angiopoietin-2 (Ang2) mRNA and protein levels in HGPS mouse models.
- In vitro experiments involving the addition of Ang2 to HGPS endothelial cells.
- Assessment of endothelial cell function, gene expression, nitric oxide bioavailability, and paracrine effects.
- Utilizing adenine base editor (ABE)-corrected HGPS cells and progerin-expressing HUVECs.
- Investigating the Ang2-Tie2-Akt signaling pathway.
Main Results:
- Angiopoietin-2 (Ang2) was identified as a down-regulated signaling molecule in HGPS endothelial cells and aortas.
- Ang2 supplementation rescued vasculogenesis, normalized endothelial cell migration and gene expression, and restored nitric oxide bioavailability in HGPS cells.
- Ang2 reversed the detrimental paracrine effects of HGPS endothelial cells on vascular smooth muscle cells.
- A negative correlation between progerin expression and Ang2 levels was observed.
- Ang2 demonstrated beneficial effects in endothelial cells via Tie2 receptor binding and Akt pathway activation.
Conclusions:
- Progerin negatively regulates Ang2 expression, contributing to endothelial cell dysfunction in HGPS.
- Ang2 plays a critical role in maintaining endothelial cell function and vascular health.
- Ang2 treatment represents a promising therapeutic strategy for cardiovascular diseases associated with Hutchinson-Gilford progeria syndrome.
Abstract:
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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