Clinical Use of Hydrogen Sulfide to Protect Against Intimal Hyperplasia

Abstract

Arterial occlusive disease is the narrowing of the arteries via atherosclerotic plaque buildup. The major risk factors for arterial occlusive disease are age, high levels of cholesterol and triglycerides, diabetes, high blood pressure, and smoking. Arterial occlusive disease is the leading cause of death in Western countries. Patients who suffer from arterial occlusive disease develop peripheral arterial disease (PAD) when the narrowing affects limbs, stroke when the narrowing affects carotid arteries, and heart disease when the narrowing affects coronary arteries. When lifestyle interventions (exercise, diet…) fail, the only solution remains surgical endovascular and open revascularization. Unfortunately, these surgeries still suffer from high failure rates due to re-occlusive vascular wall adaptations, which is largely due to intimal hyperplasia (IH). IH develops in response to vessel injury, leading to inflammation, vascular smooth muscle cells dedifferentiation, migration, proliferation and secretion of extra-cellular matrix into the vessel's innermost layer or intima. Re-occlusive IH lesions result in costly and complex recurrent end-organ ischemia, and often lead to loss of limb, brain function, or life. Despite decades of IH research, limited therapies are currently available. Hydrogen sulfide (H₂S) is an endogenous gasotransmitter derived from cysteine metabolism. Although environmental exposure to exogenous high H₂S is toxic, endogenous H₂S has important vasorelaxant, cytoprotective and anti-inflammatory properties. Its vasculo-protective properties have attracted a remarkable amount of attention, especially its ability to inhibit IH. This review summarizes IH pathophysiology and treatment, and provides an overview of the potential clinical role of H₂S to prevent IH and restenosis.

Keywords: hydrogen sulfide (H2S); intimal and medial thickening; intimal hyperplasia; restenosis; vascular SMCs.

FIGURE 1

Intimal hyperplasia. In the healthy vessel (left), the inner intimal layer is composed only of the endothelium (pink layer). Under the endothelium sits the basement layer and internal elastic lamina (IEL). The media layer is composed of elastic fibers and smooth muscle cells (SMC). The outer part of the media and adventitia are separated by the exterior elastic lamina (EEL). Restenosis following vascular surgery is the formation of a neointima layer between the IEL and endothelium. It is composed of proliferating SMC-like cells of different origin and extracellular matrix (ECM).

FIGURE 2

The pathophysiology of intimal hyperplasia. IH is triggered by endothelial injury, which activates platelets aggregation, and recruitment and activation of immune cells in the arterial wall (early inflammatory phase). The platelets and immune cells release cytokines, chemokines and growth factors, which stimulate a wound healing response mediated by SMC-like cells (mostly synthetic SMC derived from medial VSMC and myofibroblasts derived from adventitial fibroblasts). These synthetic SMC-like cells proliferate and migrate under the internal elastic lamina (IEL), forming the neointima layer. Long after inflammation is resolved and the endothelium is repaired (chronic phase), these cells continue to secrete extracellular matrix (ECM), leading to the progressive narrowing of the lumen.

FIGURE 3

The benefits of hydrogen sulfide on the vascular system in the context of intimal hyperplasia.