Precis Future Med.
2023 Mar;7(1):44-54. 10.23838/pfm.2022.00135.
Angiogenesis effect of udenafil in a caveolin-1 deficient moyamoya disease model: A pre-clinical animal study
- Affiliations
-
- 1Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul, Korea
- 2CellnLife Inc., Seoul, Korea
- 3Advanced Radiation Technology Institute, Jeongeup Campus of Korea Atomic Energy Research Institute (KAERI), Jeongeup, Korea
- 4Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- 5Center for Cell Therapy, Asan Institute for Life Science, Asan Medical Center, Seoul, Korea
- 6Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- KMID: 2541463
- DOI: http://doi.org/10.23838/pfm.2022.00135
Abstract
- Purpose
Although pathogenic mechanisms of moyamoya disease (MMD) remain unknown, recent studies suggest that it is a caveolae disease. This study evaluated the effect of udenafil, a phosphodiesterase-5 inhibitor, on angiogenesis in in vitro and in vivo MMD models.
Methods
Angiogenesis and vessel maturation were assessed in in vitro models, caveolin- 1 (Cav-1) knockdown human umbilical vessel endothelial cells (HUVECs) and coronary artery smooth muscle cells (CASMCs), and in in vivo model of bilateral internal carotid artery occlusion (bICAo). Udenafil was administered (1,3,10, and 30 μM) in cell culture conditions, and functional studies (migration and tube formation assay) were performed and vessel maturation factors and cyclic guanosine monophosphate (cGMP) accumulation were measured.
Results
Udenafil (3 and 10 mg/kg) was orally administered once daily for 4 weeks in bICAo rat model, and histological analysis for angiogenesis and vessel maturation was performed. Udenafil increased vessel formation in both Cav-1 knockdown HUVEC and bICAo models without increased migration/proliferation of HUVECs and CASMCs. Udenafil increased CD31+ vessel density and NG2/Col4+ mural cell density in bICAo models. Cav-1 knockdown inhibited accumulation of cGMP, and udenafil treatment restored cGMP levels in Cav-1 knockdown HUVEC models. Vessel maturation factors (angiopoietin- 1 and platelet-derived growth factor receptor-β) and angiogenic factors (endothelial nitric oxide synthase) were increased after treatment with udenafil in vitro.
Conclusion
Our results indicate that udenafil reversed cellular levels of cGMP related to Cav-1 deficiency and induced angiogenesis and vessel maturation. Further studies are warranted to confirm the therapeutic effects of this strategy in MMD.
