Abstract
Existing vascular endothelial growth factor–oriented antiangiogenic approaches are known for their high potency. However, significant side effects associated with their use drive the need for novel antiangiogenic strategies. The small GTPase RhoA is an established regulator of actin cytoskeletal dynamics. Previous studies have highlighted the impact of endothelial RhoA pathway on angiogenesis. Rho-associate kinase (ROCK), a direct RhoA effector, is potently inhibited by Fasudil, a clinically relevant ROCK inhibitor. Here, we aimed to target the RhoA signaling in endothelial cells by generating Fasudil-encapsulated CD31-targeting liposomes as a potential antiangiogenic therapy. The liposomes presented desirable characteristics, preferential binding to CD31-expressing HEK293T cells and to endothelial cells, inhibited stress fiber formation and cytoskeletal-related morphometric parameters, and inhibited in vitro angiogenic functions. Overall, this work shows that the nanodelivery-mediated endothelial targeting of RhoA signaling can offer a promising strategy for angiogenesis inhibition in vascular-related diseases.
SIGNIFICANCE STATEMENT Systemic administration of antiangiogenic therapeutics induces side effects to non-targeted tissues. This study, among others, has shown the impact of the RhoA signaling in the endothelial cells and their angiogenic functions. Here, to minimize potential toxicity, this study generated CD31-targeting liposomes with encapsulated Fasudil, a clinically relevant Rho kinase inhibitor, and successfully targeted endothelial cells. In this proof-of-principle study, the efficient Fasudil delivery, its impact on the endothelial signaling, morphometric alterations, and angiogenic functions verify the benefits of site-targeted antiangiogenic therapy.
Footnotes
- Received July 25, 2022.
- Accepted January 17, 2023.
This work was supported for C.M.M. in part by the National Institutes of Health National Cancer Institute [Grant R15-CA231339], the Texas Tech University Health Sciences Center (TTUHSC) School of Pharmacy Office of the Sciences grant, and the Hellenic Foundation for Research and Innovation (00376), and for G.M. by the College of Pharmacy, University of Louisiana Monroe start-up funding, National Institutes of Health National Institute of General Medical Sciences [Grant P20-GM103424-21], and the Research Competitiveness Subprogram of the Louisiana Board of Regents through the Board of Regents Support Fund [LEQSF(2021-24)-RD-A-23]. The common TTUHSC equipment used was obtained through the Cancer Prevention Research Institute of Texas [Grants RP110786, RP190524, and RP200572]. The funders had no role in study design, decision to write, or preparation of the manuscript. The data were part of the Behnaz Lahooti’s PhD Thesis at TTUHSC.
The authors declare no competing interests.
↵1D.P. and S.S. contributed equally to this work.
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- Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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