Vegfa signaling ameliorates cardiac fibrosis and restores endothelial regeneration in a point-mutated zebrafish model of pseudoxanthoma elasticum

Jianjian Sun; Peilu She; Jichang Huang; Renjie Zhang; Shubin Zhang; Wenqi Chen; Tao P Zhong; Ping Zhu

doi:10.1016/j.bbrc.2025.152163

Vegfa signaling ameliorates cardiac fibrosis and restores endothelial regeneration in a point-mutated zebrafish model of pseudoxanthoma elasticum

Biochem Biophys Res Commun. 2025 Jun 6:776:152163. doi: 10.1016/j.bbrc.2025.152163. Online ahead of print.

Authors

Jianjian Sun¹, Peilu She², Jichang Huang³, Renjie Zhang⁴, Shubin Zhang⁴, Wenqi Chen⁴, Tao P Zhong⁵, Ping Zhu⁶

Affiliations

¹ Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510100, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, 200241, China; Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, 510100, China. Electronic address: jjsun@bio.ecnu.edu.cn.
² Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510100, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, 200241, China; Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, 510100, China.
³ Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510100, China; Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, 510100, China.
⁴ Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, 200241, China.
⁵ Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, 200241, China. Electronic address: tzhong@bio.ecnu.edu.cn.
⁶ Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510100, China; Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, 510100, China. Electronic address: tanganqier@163.com.

PMID: 40532309
DOI: 10.1016/j.bbrc.2025.152163

Abstract

The ABCC6 gene is associated with pseudoxanthoma elasticum (PXE), a genetic disorder characterized by ectopic calcification in soft tissues, notably affecting the cardiovascular system. However, the underlying cardiovascular pathological mechanisms remain elusive and effective treatments are currently unavailable. Here, we employed a point-mutated zebrafish model harboring the abcc6a^{R1463C/R1463C} mutation (orthologous to the human ABCC6^R1459C variant) to investigate the cardiac homeostasis and regeneration. We find that abcc6a deficiency leads to enhanced TGF-β/Smad3 signaling and vegfaa overexpression ameliorates abcc6a deficiency-induced cardiac fibrosis and mitochondrial ultrastructural defects. Moreover, abcc6a^{R1463C/R1463C} mutants exhibit coronary vasculature malformations, impaired endothelial proliferation and compromised revascularization post-cardiac injury. Transcriptomic profiling reveals upregulated genes associated with the extracellular matrix (ECM) and downregulated genes involved in signal transduction and circulatory system (vegfaa, vegfc, notch1a, notch1b, dll4). vegfaa overexpression in abcc6a^{R1463C/R1463C} mutants attenuates cardiac pathologies by restoring endothelial proliferation, resolving fibrosis, and enhancing injury repair. Mechanistically, vegfaa acts via Notch signaling to ameliorate endocardial deficits and functional impairments. Our findings establish abcc6a as a critical regulator of cardiac resilience, coordinating anti-fibrotic and pro-regenerative responses, and propose Vegfa and Notch pathways as therapeutic synergy for PXE-related cardiovascular pathophysiology.

Keywords: Notch signaling; PXE; Zebrafish; abcc6a; vegfaa.