Authors:

Jada Leonard

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The VEGF-A Splice Variants as a Mechanism of Impaired Inflammatory Angiogenesis in the Context of Advanced Aging Aging and age-related diseases like peripheral artery disease (PAD) are associated with impairment of angiogenesis and arteriogenesis in response to vascular injury. In addition to medical therapy, treatment options are largely limited to mechanical revascularization, by surgical bypass or angioplasty, but 20-25% of advanced PAD patients are ineligible, which can potentially lead to limb amputation. Thus, therapies aimed at increasing angiogenesis in PAD are being pursued as an alternative treatment strategy. Gene-based therapies using angiogenic molecules like VEGF-A have not fully restored functional vascular networks. This underscores the need to investigate further VEGF-A signaling, including VEGF-A 165 splice variants, which are currently overlooked in existing VEGF-based treatments. VEGF-A exists as two alternative splice isoforms, with opposing functions in that VEGF-A 165a is proangiogenic and VEGF-A 165b is antiangiogenic. Our preliminary data from advanced aged (2-year-old) mice showed severely impaired blood flow recovery with reduced new capillaries/arteries compared to young (12-week-old) mice in a femoral artery ligation model of PAD. This impaired recovery was associated with reduced proangiogenic VEGF-A165a expression, yet increased IL-1β and VEGF-A 165b in the ischemic muscle of aged mice. These data suggest an age-associated VEGF-A 165 splice isoform switch. VEGF-A 165 mRNA splicing occurs under the regulation of spliceosomes. We also found reduced expression of RNA binding proteins activating VEGF-A 165a (SRPK1/SRSF1 axis) and significantly increased expression of Wnt5a, which increases VEGF-A 165b expression in aged mice. Monocytes/macrophages are a major source of angiogenic mediators in CLI and wound injury animal models. We found that primary macrophages from aged mice show a comparable splice isoform switch when stimulated to express VEGF-A. However, the mechanism of action, importance, and expression levels of the VEGF-A 165 splice isoforms in health and age-related cardiovascular diseases remain unclear. We seek to investigate the molecular mechanisms of macrophage VEGF-A 165 alternative splice variants in PAD and aging in response to vascular injury. Our investigations will improve our understanding of how the VEGF-A 165 alternative splice isoform switch occurs in vivo, particularly in conditions that lead to clinical vascular diseases. Improving the balance (relative ratio) between the VEGF-A 165 splice isoforms should improve l angiogenesis/arteriogenesis as a viable strategy for cell-based therapy by reprogramming macrophages in the context of PAD and age-related defects. Jaden Carnevale:

Source:

Claflin University / Leadership Alliance-Summer Research Early Identification Program 60 (SR-EIP), First Year Research Experience (FYRE)

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Co-authors:

Jada Leonard