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<p>Moyamoya disease (MMD) is caused by abnormal vascular development. Guanylate cyclase soluble subunit alpha-1 (<i>GUCY1A3</i>) gene variation is verified as a crucial susceptible gene in MMD. In this study, we investigated the impact of <i>GUCY1A3</i> on angiogenesis. <i>GUCY1A3</i>-knockout (KO) models were established using CRISPR/Cas9 technology in zebrafishes and mice. Blood vessel distribution in <i>GUCY1A3</i>-KO zebrafishes and retinal angiogenesis in postnatal <i>GUCY1A3</i>-KO mice were analyzed. Anti-angiogenic behaviors, including cell proliferation, migration, and apoptosis, and changes in hypoxia-inducible factor-1α (HIF-1α) distribution were examined in <i>GUCY1A3</i>-knockdown (KD) mice brain microvascular endothelial cells (BMECs). <i>GUCY1A3</i>-KO significantly decreased intracranial central artery development in zebrafishes, delayed retinal vascularization in mice, reduced retinal vascular endothelial growth factor A (VEGFA) expression in mice, and abolished expression of the <i>GUCY1A3</i>-encoded protein, α1 subunit of soluble guanylate cyclase. <i>GUCY1A3</i>-KD significantly decreased cell proliferation (flow cytometry analysis) and migration (wound-healing and Transwell assays), but increased apoptosis (hypoxia-induced apoptosis assay) in the BMECs. Immunofluorescence of HIF-1α revealed that nuclear translocation and protein expression were significantly reduced in the <i>GUCY1A3</i>-KD BMECs. These findings indicated that decreased expression of <i>GUCY1A3</i> resulted in anti-angiogenic activity through inhibiting VEGFA and HIF-1α expression and nuclear translocation, inhibiting endothelial cell proliferation and migration, and promoting endothelial cell apoptosis.</p>

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The Guanylate Cyclase Soluble Subunit Alpha-1 Deficiency Impairs Angiogenesis in Zebrafishes and Mice: In Vivo and In Vitro Studies

  • 期刊论文

  • 发表日期：

    2025年2月24日

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  • Man Luo,
  • Dongcan Mo,
  • Jianli Li,
  • LiuYu Liu,
  • Xiaoling Li,
  • Jing Lin,
  • Jie Liang,
  • Fei Ye,
  • Xiaozuo Lin,
  • Pingkai Wang,
  • Xiaoju Wu,
  • Yinan Zeng,
  • Jiaoxing Li,
  • Wenli Sheng

摘要

Moyamoya disease (MMD) is caused by abnormal vascular development. Guanylate cyclase soluble subunit alpha-1 (GUCY1A3) gene variation is verified as a crucial susceptible gene in MMD. In this study, we investigated the impact of GUCY1A3 on angiogenesis. GUCY1A3-knockout (KO) models were established using CRISPR/Cas9 technology in zebrafishes and mice. Blood vessel distribution in GUCY1A3-KO zebrafishes and retinal angiogenesis in postnatal GUCY1A3-KO mice were analyzed. Anti-angiogenic behaviors, including cell proliferation, migration, and apoptosis, and changes in hypoxia-inducible factor-1α (HIF-1α) distribution were examined in GUCY1A3-knockdown (KD) mice brain microvascular endothelial cells (BMECs). GUCY1A3-KO significantly decreased intracranial central artery development in zebrafishes, delayed retinal vascularization in mice, reduced retinal vascular endothelial growth factor A (VEGFA) expression in mice, and abolished expression of the GUCY1A3-encoded protein, α1 subunit of soluble guanylate cyclase. GUCY1A3-KD significantly decreased cell proliferation (flow cytometry analysis) and migration (wound-healing and Transwell assays), but increased apoptosis (hypoxia-induced apoptosis assay) in the BMECs. Immunofluorescence of HIF-1α revealed that nuclear translocation and protein expression were significantly reduced in the GUCY1A3-KD BMECs. These findings indicated that decreased expression of GUCY1A3 resulted in anti-angiogenic activity through inhibiting VEGFA and HIF-1α expression and nuclear translocation, inhibiting endothelial cell proliferation and migration, and promoting endothelial cell apoptosis.