Abstract
Beyond their role in pathogen recognition and the initiation of immune defense, Toll-like receptors (TLRs) are known to be involved in various vascular processes in health and disease. We investigated the potential of the lipopeptide and TLR2/6 ligand macrophage activating protein of 2-kDA (MALP-2) to promote blood flow recovery in mice. Hypercholesterolemic apolipoprotein E (Apoe)-deficient mice were subjected to microsurgical ligation of the femoral artery. MALP-2 significantly improved blood flow recovery at early time points (three and seven days), as assessed by repeated laser speckle imaging, and increased the growth of pre-existing collateral arteries in the upper hind limb, along with intimal endothelial cell proliferation in the collateral wall and pericollateral macrophage accumulation. In addition, MALP-2 increased capillary density in the lower hind limb. MALP-2 enhanced endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) release from endothelial cells and improved the experimental vasorelaxation of mesenteric arteries ex vivo. In vitro, MALP-2 led to the up-regulated expression of major endothelial adhesion molecules as well as their leukocyte integrin receptors and consequently enhanced the endothelial adhesion of leukocytes. Using the experimental approach of femoral artery ligation (FAL), we achieved promising results with MALP-2 to promote peripheral blood flow recovery by collateral artery growth.
Highlights
Cardiovascular diseases are still one of the most common causes of morbidity and mortality worldwide
Since the functional improvement of macrophage-activating lipopeptide of 2 kDa (MALP-2) in the femoral artery ligation (FAL) model was limited to apolipoprotein E (Apoe)-KO mice on a high fat diet (HFD), we concluded that hypercholesterolemic conditions with compromised vascular functions are required for the observed beneficial effects of MALP-2; we focused on this model in the following analysis
Atherosclerosis, as a chronic inflammatory arterial disease, contributes to the major mortality of cardiovascular diseases worldwide. This is due to acute events such as myocardial infarction and strokes [23], but on the other, this is due to progressive lumen stenosis, which is the main trigger for adaptive arteriogenesis [4,5,6,18]
Summary
Cardiovascular diseases are still one of the most common causes of morbidity and mortality worldwide. In this regard, atherosclerosis—a chronic inflammatory disease of the arteries—has long been identified as the underlying cause that could lead to fatal events such as myocardial infarction, strokes [1] and to peripheral artery disease (PAD) [2]. The growth of pre-existing collateral arteries ( termed as arteriogenesis) represents an endogenous mechanism of bypassing occluded vessels and is an important adaptive response to maintain or restore arterial perfusion [4]. Arteriogenesis occurs in tissues near to arterial stenosis whereas down-stream ischemic regions undergo angiogenesis, which is the growth of new capillaries.
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