Abstract Body: Diabetes mellitus (DM) is a chronic disease and a major health problem worldwide, especially in elderly people (>65 years). Patients with chronic DM suffer from vascular complications including heart failure, coronary heart disease and peripheral artery disease (PAD). DM and aging are important risk factors of PAD. DM increases the risk of developing PAD while PAD contributes to the progression of DM. PAD-mediated DM (PAD-DM) is associated with reduced blood supply and revascularization to the lower limbs resulting in limb amputation or immobility. Current treatment options are largely limited to mechanical revascularization, by surgical bypass or angioplasty, and medical management. Critical limb ischemia in PAD-DM and wound injury animal models have shown the impact of monocytes/macrophages as a major source of angiogenic mediators like the vascular endothelial growth factor (VEGF-A) and IL-1beta (IL-1β). However, pre- and clinical investigations involving VEGF-A modestly improved revascularization, but arteriogenesis restoration was incomplete in humans and animal models.
We have defined a key mechanism whereby macrophage IL-1β promotes VEGF-A expression under the regulation of transcription factors (NF-κB and STAT3) in young mice. Our data from Type 2 diabetes mellitus (TD2M) experimental mouse model, leptin receptor (Lepr^db/db) at 12-week-old demonstrated delayed blood flow recovery and new capillary growth versus young control, using a PAD model of femoral artery ligation. “Aged” 56-week-old control mice also showed reductions in blood flow recovery and angiogenesis. Moreover, combining aging with long-term diabetes, 56-week-old T2DM mice, led to further reductions in blood flow recovery consequently to impaired angiogenesis. RNA sequencing data from polarized macrophages and single nucleus RNA sequencing data from ischemic muscle tissue (gastrocnemius) from “aged” T2DM mice, showed a significant increase of Cxcl2-NLRP3 inflammasome signaling while with IL-1 receptor; MyD88 and VEGF-A expressions were reduced compared to aged control. Here, we aim to define the molecular mechanisms of altered inflammatory angiogenesis in response to vascular injury related to 1) an exacerbated and deleterious inflammation (Cxcl2-NLRP3-IL1β) and 2) a reduction in healing process (MyD88; Msi2-TGF-β signaling) in the setting of long-term diabetes mellitus. Potential results will lead to new strategies to improve neo/revascularization in PAD-DM and age-related defects.