Inhibition of VEGF (Vascular Endothelial Growth Factor)-A or its Receptor Activity Suppresses Experimental Aneurysm Progression in the Aortic Elastase Infusion Model

Abstract

Objective: We examined the pathogenic significance of VEGF (vascular endothelial growth factor)-A in experimental abdominal aortic aneurysms (AAAs) and the translational value of pharmacological VEGF-A or its receptor inhibition in aneurysm suppression. Approaches and Results: AAAs were created in male C57BL/6J mice via intra-aortic elastase infusion. Soluble VEGFR (VEGF receptor)-2 extracellular ligand-binding domain (delivered in Ad [adenovirus]-VEGFR-2), anti–VEGF-A mAb (monoclonal antibody), and sunitinib were used to sequester VEGF-A, neutralize VEGF-A, and inhibit receptor tyrosine kinase activity, respectively. Influences on AAAs were assessed using ultrasonography and histopathology. In vitro transwell migration and quantitative reverse transcription polymerase chain reaction assays were used to assess myeloid cell chemotaxis and mRNA expression, respectively. Abundant VEGF-A mRNA and VEGF-A–positive cells were present in aneurysmal aortae. Sequestration of VEGF-A by Ad-VEGFR-2 prevented AAA formation, with attenuation of medial elastolysis and smooth muscle depletion, mural angiogenesis and monocyte/macrophage infiltration. Treatment with anti–VEGF-A mAb prevented AAA formation without affecting further progression of established AAAs. Sunitinib therapy substantially mitigated both AAA formation and further progression of established AAAs, attenuated aneurysmal aortic MMP2 (matrix metalloproteinase) and MMP9 protein expression, inhibited inflammatory monocyte and neutrophil chemotaxis to VEGF-A, and reduced MMP2, MMP9, and VEGF-A mRNA expression in macrophages and smooth muscle cells in vitro. Additionally, sunitinib treatment reduced circulating monocytes in aneurysmal mice. Conclusions: VEGF-A and its receptors contribute to experimental AAA formation by suppressing mural angiogenesis, MMP and VEGF-A production, myeloid cell chemotaxis, and circulating monocytes. Pharmacological inhibition of receptor tyrosine kinases by sunitinib or related compounds may provide novel opportunities for clinical aneurysm suppression.

Bioinformatics analysis of microRNA profiles and identification of microRNA-mRNA network and biological markers in intracranial aneurysm

“…Li et al have verified that when binding with its receptors, VEGFA contribute to abdominal aortic aneurysm formation by multiple ways, for instance, suppressing mural angiogenesis, producing matrix metalloproteinase and inducing myeloid cell as well as monocytes chemotaxis. [ 32 ] The similar functions of VEGFA in IA have also been found in IA by a different group. [ 33 ]…”

Liraglutide, a TFEB‐Mediated Autophagy Agonist, Promotes the Viability of Random‐Pattern Skin Flaps

“…Angiogenesis is a complex and tightly controlled process. VEGF specifically promotes the dilation, proliferation, and migration of endothelial cells, which is directly related to angiogenesis [ 40 ], with MMP9 being a major contributor to VEGF release and angiogenesis [ 41 ]. In addition, calcium adheres to death protein 5 to promote endothelial cell connections and prevent nascent blood vessel breakdown [ 42 ].…”

Daphnetin suppresses experimental abdominal aortic aneurysms in mice via inhibition of aortic mural inflammation

“…Kaneko et al (50) found that inhibition of vascular endothelial growth factor A(VEGF-A) by soluble VEGF-A receptor-1 attenuates experimental AAA (48) reviewed studies on the role of angiogenesis in AAA and demonstrated that angiogenesis plays important roles in AAA progression. Recently, anti-angiogenesis therapy has been used as a potential intervention to treat AAA (48,51,52). DAP treatment may therefore suppress AAA via impaired mural leukocyte infiltration and angiogenesis during aneurysm formation and progression.…”