Sharma Sheila, Pierce Julia, Neverson Jade C, Khan Rachel, Lee Cadence F, Uppuluri Saketh, Parry Crystal, Amelotte Elizabeth, Butler Celia A, Sellke Frank W, Harrington Elizabeth O, Choudhary Gaurav, Morrison Alan R, Mantsounga Chris S
Vascular Research Laboratory, Providence VA Medical Center, Providence, RI 02908, USA.
Ocean State Research Institute, Inc., Providence, RI 02908, USA.
Biomedicines. 2025 Mar 31;13(4):828. doi: 10.3390/biomedicines13040828.
Peripheral artery disease is associated with significant morbidity and mortality. Mechanical revascularization strategies are a mainstay of treatment but are often limited by the anatomic complexity of atherosclerotic lesions. Therapeutic angiogenesis has fallen short of being impactful due to fundamental gaps in our understanding of postdevelopmental angiogenesis. Using a preclinical model of peripheral artery disease involving acute vascular injury by femoral artery ligation along with cellular and molecular studies of VEGF-A expression, we sought to further understand the early role of macrophages in inflammatory angiogenesis and arteriogenesis. Macrophage depletion studies revealed that the optimal levels of tissue VEGF-A expression, endothelial cell recruitment, and blood flow recovery were dependent on early macrophage recruitment. Proangiogenic VEGF-A expression was highest in macrophages polarized towards an inflammatory phenotype. Myeloid VEGF-A-deletion, while having no impact on the potent inflammatory cytokine, IL-1β, led to reductions in ischemic tissue VEGF-A, endothelial cell recruitment, and blood flow recovery due to impaired angiogenesis and arteriogenesis. Transplant of inflammatory polarized macrophages rescued the myeloid VEGF-A-deletion phenotype, leading to full blood flow recovery. Macrophages are a necessary and sufficient source of tissue VEGF-A during inflammatory-driven angiogenesis and arteriogenesis in response to vascular injury. Although further study is needed, cell-based therapeutic angiogenesis strategies involving the polarization of macrophages toward an inflammatory state, in order to produce high levels of proangiogenic VEGF-A, may be quite effective for improving revascularization in the context of PAD.
外周动脉疾病与显著的发病率和死亡率相关。机械血运重建策略是治疗的主要手段，但常常受到动脉粥样硬化病变解剖复杂性的限制。由于我们对发育后血管生成的理解存在根本性差距，治疗性血管生成尚未产生显著影响。利用一种外周动脉疾病的临床前模型，该模型涉及通过股动脉结扎造成急性血管损伤，并对VEGF-A表达进行细胞和分子研究，我们试图进一步了解巨噬细胞在炎症性血管生成和动脉生成中的早期作用。巨噬细胞清除研究表明，组织VEGF-A表达、内皮细胞募集和血流恢复的最佳水平取决于早期巨噬细胞的募集。向炎症表型极化的巨噬细胞中促血管生成VEGF-A的表达最高。骨髓VEGF-A缺失虽然对强效炎症细胞因子IL-1β没有影响，但由于血管生成和动脉生成受损，导致缺血组织VEGF-A、内皮细胞募集和血流恢复减少。炎症极化巨噬细胞的移植挽救了骨髓VEGF-A缺失表型，使血流完全恢复。在对血管损伤的炎症驱动的血管生成和动脉生成过程中，巨噬细胞是组织VEGF-A的必要且充分来源。尽管还需要进一步研究，但基于细胞的治疗性血管生成策略，即促使巨噬细胞向炎症状态极化以产生高水平的促血管生成VEGF-A，可能对改善外周动脉疾病情况下的血运重建非常有效。
