PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation.
PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation.
复制标题
DOI：
10.1007/s10456-018-9634-5
复制
发表时间：
2018-11
期刊：
影响因子：
9.8
通讯作者：
Banfi A
中科院分区：
文献类型：
--
作者：
Gianni-Barrera R;Butschkau A;Uccelli A;Certelli A;Valente P;Bartolomeo M;Groppa E;Burger MG;Hlushchuk R;Heberer M;Schaefer DJ;Gürke L;Djonov V;Vollmar B;Banfi A
VEGF诱导正常或异常的血管生成，这取决于其在体内每个产生细胞周围的微环境中的剂量。这种转变取决于VEGF诱导的内皮刺激和PDGF-BB介导的周细胞募集之间的平衡，并且尽管VEGF剂量高，但PDGF-BB的共表达使异常血管生成正常化。我们最近发现，血管内皮生长因子过度表达诱导血管生成骨骼肌通过最初的周向血管扩大，然后纵向分裂，而不是发芽。在这里，我们研究了PDGF-BB共表达使VEGF诱导的异常血管生成正常化的细胞机制。将单独或与PDGF-BB一起表达类似高水平VEGF的转导成肌细胞的单克隆群体植入小鼠骨骼肌中。PDGF-BB共表达不促进通过血管扩大和分裂发生的发芽和血管生成。然而，由于内皮细胞增殖的显著减少，增大的直径显著较小，并且保留了周细胞，否则单独使用高VEGF会丢失周细胞。组织学分析和重复活体成像的时间过程表明，PDGF-BB共表达预期血管扩张的开始，并显着加速分裂过程。有趣的是，在体内成像过程中的定量表明，剪切应力的整体降低有利于在VEGF诱导的分裂血管生成过程中启动经腔柱形成。靶基因表达的定量显示，与单独VEGF相比，PDGF-BB共表达显著降低了VEGF-R2信号传导输出。总之，PDGF-BB共表达通过调节VEGF-R2信号传导和内皮细胞增殖来防止VEGF诱导的异常血管生成，从而限制了周向扩大的程度，并使得尽管VEGF剂量高，血管分裂成正常毛细血管网络的有效完成成为可能。
VEGF induces normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo. This transition depends on the balance between VEGF-induced endothelial stimulation and PDGF-BB-mediated pericyte recruitment, and co-expression of PDGF-BB normalizes aberrant angiogenesis despite high VEGF doses. We recently found that VEGF over-expression induces angiogenesis in skeletal muscle through an initial circumferential vascular enlargement followed by longitudinal splitting, rather than sprouting. Here we investigated the cellular mechanism by which PDGF-BB co-expression normalizes VEGF-induced aberrant angiogenesis. Monoclonal populations of transduced myoblasts, expressing similarly high levels of VEGF alone or with PDGF-BB, were implanted in mouse skeletal muscles. PDGF-BB co-expression did not promote sprouting and angiogenesis that occurred through vascular enlargement and splitting. However, enlargements were significantly smaller in diameter, due to a significant reduction in endothelial proliferation, and retained pericytes, which were otherwise lost with high VEGF alone. A time-course of histological analyses and repetitive intravital imaging showed that PDGF-BB co-expression anticipated the initiation of vascular enlargement and markedly accelerated the splitting process. Interestingly, quantification during in vivo imaging suggested that a global reduction in shear stress favored the initiation of transluminal pillar formation during VEGF-induced splitting angiogenesis. Quantification of target gene expression showed that VEGF-R2 signaling output was significantly reduced by PDGF-BB co-expression compared to VEGF alone. In conclusion, PDGF-BB co-expression prevents VEGF-induced aberrant angiogenesis by modulating VEGF-R2 signaling and endothelial proliferation, thereby limiting the degree of circumferential enlargement and enabling efficient completion of vascular splitting into normal capillary networks despite high VEGF doses.
登录
查看更多内容
影响因子：
3.1
作者：
Filipovic, Nenad;Tsuda, Akira;Mentzer, Steven J.
通讯作者：
Mentzer, Steven J.
影响因子：
3.1
作者：
BAKER, M;WAYLAND, H
通讯作者：
WAYLAND, H
影响因子：
11.4
作者：
Goumans, MJ;Valdimarsdottir, G;ten Dijke, P
通讯作者：
ten Dijke, P
影响因子：
9.8
作者：
Makanya, Andrew N.;Hlushchuk, Ruslan;Djonov, Valentin G.
通讯作者：
Djonov, Valentin G.
影响因子：
9.8
作者：
Gianni-Barrera, Roberto;Trani, Marianna;Banfi, Andrea
通讯作者：
Banfi, Andrea