Dataset Information

Semaphorin 7A Promotes VEGFA/VEGFR2-Mediated Angiogenesis and Intraplaque Neovascularization in ApoE-/- Mice.

ABSTRACT: Excessive neovascularization of atherosclerotic lesions increases plaque vulnerability and the susceptibility to rupture. Semaphorin 7A (Sema7A), a semaphorin family member, was recently reported to promote atherosclerotic plaque formation by mediating d-flow-induced endothelial phenotypic change and leukocyte adhesion. To extend our understanding of the proatherogenic role of Sema7A, we investigated the role of endothelial Sema7A in angiogenesis and atherosclerotic neovascularization. Sema7A overexpression in human umbilical vein endothelial cells (HUVECs) significantly upregulated VEGFA/VEGFR2 and promoted cell migration and angiogenesis. This enhancing effect was eliminated by the blockage of Sema7A receptor, ?1 integrin. Inhibition of FAK or ERK1/2 downstream of ?1 integrin signaling significantly inhibited cell migration and angiogenesis via ROCK (Rho-associated coiled forming protein kinase) and MYPT (myosin phosphatase targeting subunit), which are responsible for actin polymerization. Consistently, in vivo studies showed a remarkable reduction in VEGFA/VEGFR2 expression and neovascularization in the atherosclerotic plaques of Sema7A-/-ApoE-/- mice compared with Sema7A+/+ApoE-/- littermates. Supportively, Sema7A deficiency reduced the accumulation of T cells, macrophages, and dendritic cells, and enhanced plaque stability in ApoE-/- mice. Together, our findings show that Sema7A promotes VEGFA/VEGFR2-mediated neovascularization in a ?1 integrin-dependent manner, supporting a crucial role of Sema7A in the progression of human atherosclerosis.

SUBMITTER: Hu S

PROVIDER: S-EPMC6284023 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Semaphorin 7A Promotes VEGFA/VEGFR2-Mediated Angiogenesis and Intraplaque Neovascularization in <i>ApoE<sup>-/-</sup></i> Mice.

Hu Shuhong S Liu Yifei Y You Tao T Zhu Li L

Frontiers in physiology 20181130

Excessive neovascularization of atherosclerotic lesions increases plaque vulnerability and the susceptibility to rupture. Semaphorin 7A (Sema7A), a semaphorin family member, was recently reported to promote atherosclerotic plaque formation by mediating d-flow-induced endothelial phenotypic change and leukocyte adhesion. To extend our understanding of the proatherogenic role of Sema7A, we investigated the role of endothelial Sema7A in angiogenesis and atherosclerotic neovascularization. Sema7A ov ...[more]

PMID: 30555351

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Project description:BackgroundBreast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear.MethodsThe prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model.ResultsACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs.ConclusionsOur findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway.Trial registrationRetrospectively registered.

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Dataset Information

Semaphorin 7A Promotes VEGFA/VEGFR2-Mediated Angiogenesis and Intraplaque Neovascularization in ApoE-/- Mice.

Publications

Semaphorin 7A Promotes VEGFA/VEGFR2-Mediated Angiogenesis and Intraplaque Neovascularization in <i>ApoE<sup>-/-</sup></i> Mice.

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