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Review
. 2015 Jan 30;116(3):480-8.
doi: 10.1161/CIRCRESAHA.116.303805.

The Role of Autophagy in Vascular Biology

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Free PMC article
Review

The Role of Autophagy in Vascular Biology

Samuel C Nussenzweig et al. Circ Res. .
Free PMC article

Abstract

There is increasing interest in the role of autophagic flux in maintaining normal vessel wall biology and a growing suspicion that autophagic dysregulation may be a common pathway through which vascular aging and associated pathologies develop. Within endothelial and smooth muscle cells, diverse but important triggers that range from oxidized lipids to β-amyloid seem to stimulate autophagosome formation potently. In addition, emerging evidence links autophagy to a wide array of vascular processes ranging from angiogenesis to calcification of the vessel wall. Alterations in autophagic flux are also increasingly being implicated in disease processes that include both atherosclerosis and pulmonary hypertension. Finally, recent insights point toward an important role of autophagy in the paracrine regulation of vasoactive substances from the endothelium. Here, we review the progress in understanding how autophagy can contribute to vascular biology and the emerging strategies to target this process for therapeutic benefit.

Keywords: aging; angiogenesis effect; autophagy; endothelial cells.

Figures

Figure 1
Figure 1
Stimulation of autophagy occurs through MTOR-dependent and MTOR-independent pathways within vascular cells. Complex I of MTOR (mTORC1) is a well characterized, negative regulator of autophagosome formation. The classical autophagic stimulus of nutrient withdrawal is believed to be largely transduced through this pathway, while the pharmacological agent rapamycin works as an inhibitor of MTOR, thereby relieving the tonic autophagic-inhibition of MTORC1. Other agents such as ER stress, ROS and oxidized lipids appear to largely work through a mix of both MTOR-dependent and MTOR-independent pathways, although the precise mechanism of action for these stimuli is largely unknown. (Illustration Credit: Ben Smith).
Figure 2
Figure 2
Lipid metabolism in macrophages involves autophagy. Evidence suggests that lipid droplets within macrophages can be engulfed by autophagosomes. Following fusion with lysosomes, lysosomal acid lipases (purple triangles) can degrade the lipid contained within the autophagosome, contributing to cholesterol efflux from the macrophage. The physiological importance of this pathway is highlighted by the observation that conditional deletion of essential autophagy genes within macrophages exacerbates atherogenesis (see text for details). (Illustration Credit: Ben Smith).
Figure 3
Figure 3
Endothelial disruption of autophagic flux impairs WPB formation. Graphical illustration of the normal maturation and secretion of VWF within endothelial cells (top). Following deletion of Atg7 or Atg5 within the endothelium (bottom), there is no change in the level of VWF, but more is found in the ER and Golgi and less within the mature WPB. Moreover, perhaps due to impaired ER and Golgi homeostasis, the pH of the WPB is altered in the absence of autophagy, leading to a shorter and more rounded morphology. Electron micrographs of these different WPB morphologies are shown (reprinted with permission from reference #64).
Figure 4
Figure 4
The convergence of autophagic flux and vascular aging. A variety of intrinsic and extrinsic factors (age, glucose, lipids, etc.) can regulate vascular autophagy. The induction of autophagy may be important in minimizing the damage these factors can induce. With increasing age, vascular autophagic flux appears to decline and this decline may contribute to the impairment in endothelial function (with decreased NO signaling) and to the increase in vascular stiffness. Efforts to maintain and augment vascular autophagy may prove to be therapeutically beneficial.

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