Abstract
There is ample evidence from epidemiological studies to suggest a relationship between psychological stress and morbidity/mortality from atherosclerosis [Holmes et al. 2006]. There is also a suggestion that psychological stress mediated via sympathetic stimulation may lead to initiation and/or progression of atherosclerosis in primates [Manuck et al. 1988]. Over 20 years ago, Lichtor and colleagues demonstrated reduction in diet-induced atherosclerosis with sympathectomy in rhesus monkeys [Lichtor et al. 1987]. These authors also showed that sympathetic blockade with propranolol reduced the progression of atherosclerosis.
Although activation of the hypothalamic-pituitary axis in response to stress [O’Connor et al. 2000] has been proposed as a link between psychological stress and atherogenesis [Nijm and Jonasson, 2009], precise patho-anatomic pathways linking these in the arterial wall have not been well defined. While purely conjectural, we hypothesize that a neuronal reflex arc involving arterial-wall innervations is an important link between psychological stress and the pathobiology of atherosclerosis, and the evolution of its complications, such as plaque rupture and erosion. In addition, the presence of this reflex in the arterial wall may provide a potential mechanism as to how traditional risk factors, for example, smoking, shear stress, and dyslipidemia, play a role in the evolution of this common malady.
Anatomically, the autonomic nervous system is organized into a supraspinal region with the hypothalamus as a master regulator and spinal level with segmental outflow [Barry et al. 2007, 2003]. Axon reflex is a neuronal reflex arc at the tissue level. This reflex, mediated through substance P [Lembeck and Holzer, 1979], and calcitonin gene-related peptide (CGRP)-rich neurons, involves activation of peripheral nerve fiber endings, which then leads to retrograde activation of the neuron bypassing the spinal and supraspinal pathways (Figure 1). Axon reflex has been described in inflammatory diseases affecting the skin [Bickel et al. 2009], eye [Todd, 1980], dental pulp [Andrew and Matthews, 2002], bronchial mucosa [Szekely and Pataki, 2009], and gastroesophageal junction [Canning and Mazzone, 2003]. Modulation of autonomic tone by supraspinal pathways and spinal reflexes is well known [Strack et al. 1989; Romagnano and Hamill, 1984; Franz et al. 1982].
The figure depicts the participation of nerve fibers in mediating axon reflex in vessel walls and its interaction with atherogenic factors. It shows how substance P and CGRP influence inflammatory cells and vessel-wall components leading to atherogenesis. In addition to interaction with a sympathetic neuron, influence by supraspinal and spinal output is depicted (refer to the text for further details). ATP, adenosine triphosphate; Ang II AT1R, angiotensin II type 1 receptor; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglion; EC, endothelial cell; IFN-γ, interferon-gamma; IL-1, interleukin-1; IL-2, interleukin-2; IL-6, interleukin-6; LDL, low-density lipoprotein; LOX-1, lectin-like oxidized-LDL receptor-1; NE, norepinephrine; NPY, neuropeptide Y; Ox-LDL, oxidized LDL; PR, purinergic receptor; SMC, smooth muscle cell; SP, substance P; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-alpha; Y1, Y2, receptor subtypes for neurotransmitter NPY with a role in axon reflex; α1, α2, alpha-1 and alpha-2 adrenoceptors.
Nerve fibers containing both substance P and CGRP have been described in human coronary arteries [Gulbenkian et al. 1993]. We propose that atherogenesis involves an abnormality in the control of sensory neurons by sympathetic nerve fibers (Figure 1). This is akin to the modulation of sensory neurons by sympathetic innervation mediated via alpha-adrenergic and angiotensin II type 1 receptors in the renal arteries [Kopp et al. 2007], leading to spontaneous hypertension in rats [Kopp et al. 2011]. Neuropeptide Y, another neurotransmitter released from sympathetic nerve endings, also has receptors on sensory neurons [Zhang et al. 1997; Brain and Cox, 2006]. In addition, there is evidence for the regulation of sensory neurons by sympathetic nerve fibers mediated via purinergic receptors (PRs) [Lomax and Vanner, 2010].
We suggest that traditional risk factors for atherosclerosis, such as smoking, hypertension, and diabetes, interact with sensory neurons and activate the axon reflex (Figure 1). There is evidence that exposure to tobacco smoke leads to an increased number of substance P-expressing neurons projecting into central pathways [Sekizawa et al. 2008]. In addition, shear stress resulting in the release of adenosine triphosphate from endothelial cells has been shown to activate sensory neurons via PRs [Burnstock, 1999]. More recently, oxidized low-density lipoprotein (LDL) has been shown to lead to sensory neuronal injury potentially mediated via toll-like receptors [Nowicki et al. 2010], or lectin-like oxidized-LDL receptors [Vincent et al. 2009].
Spatial and functional proximity of sensory neurons with inflammatory cells (Figure 1) has been described in tissue inflammation [O’Connor et al. 2004; Keeble and Brain, 2004]. Sensory neurons store and release interleukin-6, which further suggests their role in inflammation [Nordlind et al. 1995]. This close association between inflammation and the peripheral nervous system, the so-called ‘neuro-immune interaction’ has been described in skin allergy [Cevikbas et al. 2007]. It is possible that this ‘neuro-immune interaction’ exists in the arterial walls as well, although there are no scientific data so far to support this hypothesis [Ghenev and Chaldakov, 1997].
Based on the above discussion, we believe that the axon reflex in the arterial wall provides a ‘common pathway’ for traditional risk factors and psychological stress to stimulate vessel-wall inflammation, and thus play a putative role in the evolution of atherosclerosis and its complications.
Diabetes and chronic kidney disease are two common conditions associated with progressive atherogenesis; these disease states are also characterized by the presence of autonomic neuronopathy [Vinik et al. 2003; Robinson and Carr, 2002]. It is conceivable that dysautonomia in these conditions affects the micro-environment of the arterial wall, and predisposes the arterial channels to progressive and extensive atherosclerosis. The concept of arterial axon reflex may also help to understand the pathogenesis of in-stent restenosis. Mehran and colleagues showed that a common pattern of restenosis involves extension beyond the stented segment [Mehran et al. 1999]. It is possible that the extension of restenosis beyond the stented segment is mediated by the presence and activation of a local axon reflex, though the link has not been yet established.
We believe that there is much need for studies to explore how the traditional risk factors and psychological stress act to transduce signals to afferent neurons and potentially trigger axon reflex in the arterial wall.
A recent United Nations general assembly meeting declared the scourge of noncommunicable diseases as a ‘slow moving disaster’ [Rosenbaum and Lamas, 2011]. Atherosclerosis-related diseases constitute a significant part of this disaster in the making. Many studies have suggested that life-style changes may lead to regression of atherosclerosis [Ornish et al. 1990]. Thus, it becomes imperative to understand the link between risk factors and atherosclerosis in order to develop novel therapies.