AMP-Activated Protein Kinase α1 in Macrophages Promotes Collateral Remodeling and Arteriogenesis in Mice In Vivo

Abstract

A rteriogenesis is a process of developing collateral circulation through the remodeling and growth of pre-existing collateral arteries after elevated shear stress induced by occlusion.1-3 Arteriogenesis takes place both during embryogenesis and in adult tissues. In the latter case, arteriogenesis, which usually occurs at sites of occlusion or physical disruption of pre-existing arterial conduits such as coronary artery occlusion or femoral artery ligation, plays a vital role in recovery from ischemic insults. 4,5 Understanding the biological factors that affect arteriogenesis will aid in the development of new treatments for patients with arterial stenosis and occlusions.There are 2 commonly considered mechanisms for arteriogenesis: expansion of pre-existing collaterals and de novo arteriogenesis. 2,6,7 Inflammation caused by mechanical hemodynamic forces, such as shear stress and circumferential wall tension, is considered a pivotal trigger and driver for arteriogenesis. 4,[8][9][10][11] Previous studies have shown that monocytes accumulated in the surrounding tissues of collateral vessels alter arterial occlusion. 7,[11][12][13] These macrophages are potent sources of cytokines and growth factors, which are required for natural adaptive arteriogenesis. In spite of a mounting number of putative arteriogenic factors, the exact mechanisms that regulate collateral remodeling are poorly characterized. Furthermore, the processes responsible for arteriogenesis, and its associated molecular signals are poorly understood.AMP-activated protein kinase (AMPK) is a serine/threonine kinase composed of α, β, and γ subunits. 14,15 The α subunit containing the α1 and α2 isoform is the catalytic subunit, whereas the β and γ are regulatory subunits that maintain the stability of the heterotrimer complex. As an energy sensor, AMPK is activated by various cellular stresses, such as hypoxia, nutrient deprivation, and oxidative stress. [16][17][18] Once activated, AMPK phosphorylates and regulates several downstream kinases that reduce energy demand and increase energy supply to maintain whole-body energy homeostasis. 19 In addition, AMPK also regulates many other cellular processes, including cell polarity, cell growth, and proliferation. [20][21][22] Emerging studies have demonstrated that AMPK is activated in response to shear or ischemic stress. 23,24 AMPK signaling is required for angiogenesis in vivo and in vitro. [25][26][27][28] However, there is no information on the consequences of AMPK deletion in arteriogenesis. In this study, we sought to examine the role © 2016 American Heart Association, Inc. Objective-AMP-activated protein kinase (AMPK), an energy and redox sensor, is activated in response to various cellular stresses, including hypoxia, nutrient deprivation, oxidative stress, and fluid shear stress at the site of vessel blockade. The activation of AMPK is involved in angiogenesis. However, it is unknown whether AMPK can influence arteriogenesis. Here, we demonstrate the contribution of macrophage AMPK to arteriogen...

AMP-Activated Protein Kinase α2 in Neutrophils Regulates Vascular Repair via Hypoxia-Inducible Factor-1α and a Network of Proteins Affecting Metabolism and Apoptosis

“…Although in our study the role of AMPKα2 deletion in neutrophils was more pronounced, it is possible that the AMPKα1 isoform plays a significant role in the regulation of monocyte function as described in an article published during the revision of this article. 27 …”

Metabolic regulation of macrophages during tissue repair: insights from skeletal muscle regeneration

“…Indeed, macrophages not only secrete proangiogenic but also angiostatic factors . In vivo, a recent study showed that animals deficient for 5′AMP‐activated protein kinase (AMPK)α1 in macrophages exhibit a reduced remodeling of collateral arterioles after femoral artery ligation . We previously showed that in the same deficient animals, macrophages hardly acquire the restorative anti‐inflammatory phenotype during skeletal muscle regeneration (see below section Role of AMPK in macrophages during skeletal muscle regeneration) , suggesting that restorative macrophages are required for an efficient angiogenesis during muscle regeneration.…”

The Roles of AMPK in Revascularization

“…Angiogenesis is induced by hypoxia and involves three cells: tip cells, stalk cells, and phalanx cells [3][4][5], while the main stimulus of arteriogenesis is fluid shear stress (FSS), which is sensed by endothelial cells and consequently attracts leukocytes and promotes the phenotype transformation of vascular smooth muscle cells (VSMCs) [6][7][8][9]. Signal pathways of these two ways both include vascular endothelial growth factor (VEGF) pathway and nitric oxide-(NO-) dependent pathway [10][11][12][13][14] and both of them can be regulated by a highly conserved eukaryotic kinase, 5′adenosine monophosphate-activated protein kinase (AMPK) [15][16][17]; SNF1 and SnRK1 are its orthologues in yeast and several plants [18].…”