Angiogenesis induction in Buerger's disease: a disease management double-edged sword?

Abstract

Due to unknown aetiology of Thromboangiitis obliterans (TAO), its effectively treating is challenging. However, angiogenesis induction is one of the acceptable treatments for TAO patients. Recently, we have noticed that TAO patients who were under long-term treatment with angiogenesis-inducing medication showed considerable improvement in terms of healing chronic ulcers over the course of one to 2 years of treatment. However, some of them developed dermal gangrene despite the warming of their feet, with or without palpable pulses in the extremities, and with hair growth on the affected skin. Unfortunately, following the progression of dermal gangrene, some of these patients had to undergo amputation and limb loss. During histopathological evaluation, we detected some changes in the amputee TAO patients under long-term angiogenic medical treatment that were not present in amputee TAO patients who had not received any treatment for many years. The greatest pathological changes were observed in the microvascular of the skin, appearing as a proliferation of endothelial cells, NETosis and thrombus formation inside the vessels with proliferation of endothelial cells. The immunohistochemistry for CD31 and Ki67 as markers of vascular endothelium differentiation and cell mitosis confirmed the proliferation of endothelial cells. However, in the patients who had not received any treatment for years the typical pathology view of BD, including preserved vascular architecture with infiltration of inflammatory cells and inflammatory cells inside the thrombus, organised thrombus with recanalisation and intimal thickening was observed. Further longitudinal cohort studies regarding long-term treatment with angiogenic medications for TAO in different geographic areas are highly recommended.

The Imbalance among Oxidative Biomarkers and Antioxidant Defense Systems in Thromboangiitis Obliterans (Winiwarter-Buerger Disease)

“…Interestingly, MDA plays a role, also, in angiogenesis by influencing both vascular endothelial growth factor (VEGF) expression and NO alteration [65]; therefore, our data of significantly decreased serum levels of MDA might hypothetically take part in disturbing the process of angiogenesis typical of WBD [20,66,67].…”

“…They act both directly and by generating pro-angiogenic oxidation products, mainly through HIF/VEGF signaling [79]. It is important to note that angiogenesis is a process dysregulated in WBD, and it has been demonstrated that long-term treatment with angiogenic medications for WBD in different geographic areas are highly recommended [8,66]. In this respect, angiogenesis is an efficient mechanism in WBD, and could be compromised by diminished SOD activity, mainly due to the possibility of SOD-derived H 2 O 2 to induce the VEGF signaling pathway [59,66,80].…”

“…It is important to note that angiogenesis is a process dysregulated in WBD, and it has been demonstrated that long-term treatment with angiogenic medications for WBD in different geographic areas are highly recommended [8,66]. In this respect, angiogenesis is an efficient mechanism in WBD, and could be compromised by diminished SOD activity, mainly due to the possibility of SOD-derived H 2 O 2 to induce the VEGF signaling pathway [59,66,80]. Noteworthy, it has been previously reported that VEGF signaling is altered in WBD patients, due to increased expression of specific receptor VEGF-R1 (known as an angiogenesis inhibitor) in the WBD patients and smokers vs. non-smoker subjects [10].…”

“…Finally, it has been recently demonstrated that SOD activity is higher in women than in men [81], which could help explain why men tend to be more common victims of Winiwarter-Buerger disease [4,47,66].…”

Long-Term Outcomes of Peripheral Blood Mononuclear Cells in the Treatment of Angiitis-Induced No-Option Critical Limb-Threatening Ischemia

“…Although antiplatelet, anticoagulant, statins, vasodilators, and smoking cessation are widely used in the treatment of patients with TAO, none of these treatments provided noticeable improvement ( 32 , 36 ). In addition, Fazeli et al concluded that long-term treatment with angiogenic medication may be a risk factor for dermal gangrene in patients with TAO and ultimately might be a disease management double-edged sword ( 37 ). Fang et al found that smoking cessation does not make a big difference to the symptoms of the patients when they presented CLTI.…”