The effect of statin treatment on developmental angiogenesis in zebrafish
Date
2024
DOI
Authors
Version
OA Version
Citation
Abstract
Atherosclerosis is the leading cause of cardiovascular disease globally and is characterized by the accumulation of low density lipoprotein cholesterol (LDL-C) in the sub-endothelial space of arteries. Statins have proven effective at lowering LDL-C and protecting against atherogenic risk. However, the effect of statin on early vascular development, including intussusceptive and sprouting angiogenesis, proves inconclusive suggesting both pro- and anti-angiogenic effects. In this study, we treated wild type (wt) and low-density lipoprotein receptor (ldlr) knockout (Tg:flk:GFP) zebrafish with atorvastatin and simvastatin at 1-day post fertilization (1dpf) and 24 hours later at 2-days post-fertilization (2dpf) we quantified survival (%), intracranial hemorrhage (ICH) (%), and developmental angiogenesis in the dorsal aorta (DA), caudal venous plexus (CVP) and intersegmental vessels (ISV). Our findings demonstrate ldlr mutant zebrafish treated with lethal doses of 50 nM atorvastatin and 100 nM simvastatin demonstrated a significant reduction in intersegmental vessels compared to wt. Furthermore, ldlr mutant zebrafish had significantly greater number of intussusceptive pillars in both untreated and sublethal statin treatment (10 nM atorvastatin and 1 nM simvastatin) compared to wt zebrafish. Additionally, there was a dose-dependent effect on survival and ICH for both atorvastatin and simvastatin treated wt and ldlr mutant genotypes. Moreover, ldlr homozygous mutants treated with atorvastatin but not with simvastatin demonstrated a protective effect on statin-induced lethality compared to wt zebrafish. Despite the enhanced survival of ldlr mutant zebrafish with doses of statin lethal in wild-type fish, our findings suggest an exaggerated anti-angiogenic effect for both sprouting angiogenesis and intussusceptive angiogenesis in ldlr knockout. The results presented in this work sets the foundation for mechanistic studies and further exploration of distinguishing pro-angiogenic and anti-angiogenic effects, such as looking at endothelial cell turnover and cytoskeletal structure in the characterized vascular phenotypes presented in this study.
Description
2024