Vascular autophagy in health and disease

Abstract

Homeostasis is maintained within organisms through the physiological recycling process of autophagy, a catabolic process that is intricately involved in the mobilization of nutrients during starvation, recycling of cellular cargo, as well as initiation of cellular death pathways. Specific to the cardiovascular system, autophagy responds to both chemical (e.g. free radicals) and mechanical stressors (e.g. shear stress). It is imperative to note that autophagy is not a static process, and measurement of autophagic flux provides a more comprehensive investigation into the role of autophagy. The overarching themes emerging from decades of autophagy research are that basal levels of autophagic flux are critical, physiological stressors may increase or decrease autophagic flux, and more importantly, aberrant deviations from basal autophagy may elicit detrimental effects. Autophagy has predominantly been examined within cardiac or vascular smooth muscle tissue within the context of disease development and progression. Autophagic flux within the endothelium holds an important role in maintaining vascular function, demonstrated by the necessary role for intact autophagic flux for shear-induced release of nitric oxide however the underlying mechanisms have yet to be elucidated. Within this review, we theorize that autophagy itself does not solely control vascular homeostasis, rather, it works in concert with mitochondria, telomerase, and lipids to maintain physiological function. The primary emphasis of this review is on the role of autophagy within the human vasculature, and the integrative effects with physiological processes and diseases as they relate to the vascular structure and function.

Keywords: Endothelium; Flow-mediated dilation; Macroautophagy; Mitochondria; Telomerase.

Figure 1:

Conceptual overview of shear-induced signaling pathways to elicit vasodilation in health. Laminar shear stress confers adaptive autophagy within the endothelium and vascular smooth muscle by enhancing production of NO from eNOS, minimizing mitochondria-derived ROS, ultimately eliciting NO-mediated vasodilation Abbreviations: NO, nitric oxide; ROS, reactive oxygen species; PI3K, Phosphoinositide 3-kinase; eNOS, endothelial nitric oxide synthase; L-Arg, l-arginine; sGC, soluble guanylate cyclase; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate.

Figure 2:

Disturbed shear stress, decreases in TERT, as well as elevations in LPA and ceramide confer maladaptive autophagy. Both excessive or insufficient, minimizes NO formation from eNOS, preferentially producing H₂O₂ and ultimately driving the primary mechanism of vasodilation to H₂O₂ in response to shear stress. Maladaptive autophagy may not sufficiently degrade the cellular cargo, ultimately eliciting further elevations in ROS. Abbreviations: LPA, lysophosphatidic acid; TERT, telomerase reverse transcriptase; NO, nitric oxide; ROS, reactive oxygen species; PI3K, Phosphoinositide 3-kinase; eNOS, endothelial nitric oxide synthase; PKG, protein kinase G; O₂⁻, superoxide; H₂O₂, hydrogen peroxide; BK_Ca; large conductance calcium activated potassium channel; VSM, vascular smooth muscle.