Mechanisms of angiogenic incompetence in Hutchinson-Gilford progeria via downregulation of endothelial NOS

Aging Cell. 2021 Jul;20(7):e13388. doi: 10.1111/acel.13388. Epub 2021 Jun 4.


Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder with features of accelerated aging. The majority of HGPS cases are caused by a de novo point mutation in the LMNA gene (c.1824C>T; p.G608G) resulting in progerin, a toxic lamin A protein variant. Children with HGPS typically die from coronary artery diseases or strokes at an average age of 14.6 years. Endothelial dysfunction is a known driver of cardiovascular pathogenesis; however, it is currently unknown how progerin antagonizes normal angiogenic function in HGPS. Here, we use human iPSC-derived endothelial cell (iPSC-EC) models to study angiogenesis in HGPS. We cultured normal and HGPS iPSC-ECs under both static and fluidic culture conditions. HGPS iPSC-ECs show reduced endothelial nitric oxide synthase (eNOS) expression and activity compared with normal controls and concomitant decreases in intracellular nitric oxide (NO) level, which result in deficits in capillary-like microvascular network formation. Furthermore, the expression of matrix metalloproteinase 9 (MMP-9) was reduced in HGPS iPSC-ECs, while the expression of tissue inhibitor metalloproteinases 1 and 2 (TIMP1 and TIMP2) was upregulated relative to healthy controls. Finally, we used an adenine base editor (ABE7.10max-VRQR) to correct the pathogenic c.1824C>T allele in HGPS iPSC-ECs. Remarkably, ABE7.10max-VRQR correction of the HGPS mutation significantly reduced progerin expression to a basal level, rescued nuclear blebbing, increased intracellular NO level, normalized the misregulated TIMPs, and restored angiogenic competence in HGPS iPSC-ECs. Together, these results provide molecular insights of endothelial dysfunction in HGPS and suggest that ABE could be a promising therapeutic approach for correcting HGPS-related cardiovascular phenotypes.

Keywords: ABE; aging; eNOS; endothelial cells; progeria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cellular Senescence
  • Down-Regulation
  • Endothelial Cells / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Progeria / genetics*
  • Progeria / pathology