What Went Wrong with VEGF-A in Peripheral Arterial Disease? A Systematic Review and Biological Insights on Future Therapeutics

Abstract

<b><i>Background:</i></b> Of the 200 million patients worldwide affected by peripheral arterial disease (PAD), 4% will inevitably require major limb amputation. Previous systematic reviews presented a conflicting body of evidence in terms of vascular endothelial growth factor (VEGF) family member effects upon PAD natural progression. Despite that, modulation of intrinsic angiogenesis mechanisms targeting the VEGF family members still confers an attractive therapeutic target. The aim of the present study was to evaluate current evidence of VEGF modulation in the context of PAD. <b><i>Methods:</i></b> This is a systematic literature review conducted according to the PRISMA guidelines and registered under PROSPERO database [CRD42021285988]. Independent literature search was performed up to April 1, 2022, on six databases. A total of 22 eligible studies were identified [N: 3, interventional patient studies; N: 19, animal studies]. Animal studies were appraised by the SYRCLE risk of bias tool, while human participant studies were assessed by the Newcastle Ottawa scale. Overall, quality of evidence was deemed fair for both animal and human studies. Main study outcomes were percentage change of injured vessel lumen stenosis and neointimal area formation upon VEGF modulation (inhibition or activation) in comparison with control group. <b><i>Findings:</i></b> Nineteen animal models and three human participant studies were included in the systematic review and assessed separately. Positive modulation of VEGF-A in animal models resulted in a median decrease of 65.58% [95% CI 45.2; 71.87] in lumen stenosis [14 studies]. Furthermore, positive modulation of VEGF-A was found to reduce neointimal area proliferation by a median decrease of 63.41% [95% CI 41.6; 79.59] [14 studies]. Median end of study duration was 28 days [range: 14–84 days]. Data were insufficient to assess these outcomes with respect to VEGF-B or VEGF-C modulation. The limited number of available human studies presented inadequate outcome assessment despite their overall fair NOS grading. <b><i>Interpretation:</i></b> VEGF-A-positive modulation decreases lumen stenosis and neointimal hyperplasia in PAD simulation animal models. Previously identified variability among outcomes was found to strongly stem from the variability of experimental designs. Clinical applicability and safety profile of VEGF-A in the context of PAD remain to be defined by a robust and uniformly designed body of further animal model-based experiments.

Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia

“…Although surgical and endovascular approaches to revascularization represent the primary strategy to treat PAD, outcomes remain poor, particularly in CLTI, which results in high rates of subsequent amputation (40,41). Moreover, while experimental pro-angiogenic approaches to improve limb perfusion have shown great promise in preclinical models of hindlimb ischemia, they have proven suboptimal in clinical experience (42,43). We hypothesized that these poor outcomes might be explained, at least in part, by non-vascular etiologies of CLTI.…”

Cell state transition analysis reveals a causal network that controls critical limb ischemia

“…Though myocytes comprise the greatest cell mass in muscle, it is not unreasonable to conclude that ECs drive the responses of the myocytes and the muscle as the whole in PAD. Generating functional, stable blood vessels has to be a goal of human therapeutics and generating tumor-like vessels within an ischemic muscle, whether in a mouse or a human, would be expected to be detrimental 15,16 .…”

VEGF (Vascular Endothelial Growth Factor) Inhibition and Hypertension: Does Microvascular Rarefaction Play a Role?

“…2,[18][19][20] To this end, the VEGF signaling pathway interacts with the Notch signaling pathway, and neural guidance genes expressed in the vascular system, to coordinate crucial processes such as arterial-venous differentiation, vessel sprouting and branching morphogenesis, lumen remodeling and vessel maturation. 21 Kastora et al 22 recently reviewed the microvascular growth effects of activation of the VEGF-VEGF receptor-2 system in patients with insufficient tissue perfusion due to peripheral artery disease.…”