Cutini Pablo H, Campelo Adrián E, Massheimer Virginia L
Departamento de Biología, Bioquímica y Farmacia, Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional del Sur (UNS), Bahía Blanca, Buenos Aires, Argentina.
Vasc Med. 2022 Oct;27(5):425-432. doi: 10.1177/1358863X221112168. Epub 2022 Jul 25.
Since several additional actions of bone bisphosphonates have been proposed, we studied the effect of the bisphosphonate alendronate (ALN) on the vascular response to environmental stress.
Primary cultures of endothelial cells (EC) and vascular smooth muscle cells (VSMC) exposed to strained conditions were employed for experimental evaluation. After ALN treatment, cell migration, proliferation, and angiogenesis assays were performed. The participation of signal transduction pathways in the biochemical action of ALN was also assessed.
In VSMC cultures, ALN counteracted the stimulation of cellular migration elicited by the proinflammatory agent lipopolysaccharide (LPS) or by high levels of calcium and phosphorus (osteogenic medium). Indeed, ALN reduced the increase of VSMC proliferation evoked by the stressors. When LPS and osteogenic medium were added simultaneously, the enhancement of cell proliferation dropped to control values in the presence of ALN. The mechanism of action of ALN involved the participation of nitric oxide synthase, mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) signaling pathways. The study revealed that ALN exhibits a proangiogenic action. On EC, ALN enhanced vascular endothelial growth factor (VEGF) synthesis, and induced capillary-like tube formation in a VEGF-dependent manner. The presence of vascular stress conditions (LPS or osteogenic medium) did not modify the proangiogenic action elicited by ALN.
The findings presented suggest an extra-bone biological action of ALN, which could contribute to the maintenance of vascular homeostasis avoiding cellular damage elicited by environmental stress.
由于已提出骨双膦酸盐的几种额外作用，我们研究了双膦酸盐阿仑膦酸钠（ALN）对血管对环境应激反应的影响。
采用暴露于应激条件下的内皮细胞（EC）和平滑肌细胞（VSMC）原代培养物进行实验评估。在ALN处理后，进行细胞迁移、增殖和血管生成测定。还评估了信号转导通路在ALN生化作用中的参与情况。
在VSMC培养物中，ALN抵消了促炎剂脂多糖（LPS）或高水平钙和磷（成骨培养基）引起的细胞迁移刺激。事实上，ALN减少了应激源引起的VSMC增殖增加。当同时添加LPS和成骨培养基时，在ALN存在下细胞增殖的增强降至对照值。ALN的作用机制涉及一氧化氮合酶、丝裂原活化蛋白激酶（MAPK）和蛋白激酶C（PKC）信号通路的参与。该研究表明ALN具有促血管生成作用。在EC上，ALN增强血管内皮生长因子（VEGF）合成，并以VEGF依赖的方式诱导毛细血管样管形成。血管应激条件（LPS或成骨培养基）的存在并未改变ALN引起的促血管生成作用。
所呈现的研究结果表明ALN具有骨外生物学作用，这可能有助于维持血管稳态，避免环境应激引起的细胞损伤。
