Sympathetic Nervous System and Atherosclerosis

Abstract

Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (α1, α2, β1, β2, and β3) and renal denervation on atherosclerosis. All five types of adrenoceptors are present in arterial blood vessels. α1 blockers inhibit atherosclerosis but increase the risk of heart failure while α2 agonism may protect against atherosclerosis and newer generations of β blockers and β3 agonists are promising therapies against atherosclerosis; however, new randomized controlled trials are warranted to investigate the effectiveness of these therapies in atherosclerosis inhibition and cardiovascular risk reduction in the future. The role of renal denervation in atherosclerosis inhibition in humans is yet to be established.

Keywords: alpha blocker; atherosclerosis; beta blocker; blood vessel; renal denervation; sympathetic activity.

Figure 1

Sympathetic innervation in vasculature. The sympathetic pathway is formed of two serially connected sets of neurons: preganglionic and postganglionic neurons. The preganglionic neurons originate in the brainstem or the spinal cord. They exit the spinal cord and synapse (using acetylcholine as a neurotransmitter) with postganglionic sympathetic neurons in the ganglia. The nerve endings of the postganglionic neurons branch repeatedly, forming synapses en passant (“synapses in passing”) or varicosities (knoblike swellings) containing mitochondria and synaptic vesicles. The key neurotransmitter in the synaptic vesicles of the varicosities is norepinephrine. In addition, the sympathetic preganglionic neurons synapse with chromaffin cells in the adrenal gland to stimulate the production of epinephrine and norepinephrine from the adrenal medulla. The produced epinephrine and norepinephrine then enter the blood and may affect distant blood vessels and tissues. Ach, acetylcholine; EPI, epinephrine; and NE, norepinephrine.

Figure 2

Norepinephrine biosynthesis. Tyrosine is converted by tyrosine hydroxylase (TH) to dihydroxyphenylalanine (DOPA), and the latter is converted by DOPA decarboxylase to dopamine in the cytoplasm. Dopamine is converted by dopamine β-hydroxylase to norepinephrine in the vesicles. In the adrenal medulla, norepinephrine is converted by phenylethanolamine N-methyltransferase (PNMT) to epinephrine.

Figure 3

Norepinephrine metabolism. ALDH, aldehyde dehydrogenase; ALR, aldehyde reductase; COMT, catechol-O-methyltransferase; and MAO, monoamine oxidase.

Figure 4

Illustration of norepinephrine-induced vasoconstriction via an α1 adrenoceptor. Norepinephrine binds the α1 adrenoceptor, resulting in Gq/11 activation and opening of the calcium (Ca²⁺) channel. Thus, the cytoplasmic Ca²⁺ concentration increases. In addition, Gq/11 induces inositol triphosphate (IP3) production which binds to IP3 receptors on the sarcoplasmic reticulum (SR), resulting in the release of Ca²⁺ from SR. Free Ca²⁺ then binds to calmodulin (CaM) and phosphorylates the myosin light chain (MLC), which leads to vasoconstriction. In addition, activation of the α1 adrenoceptor can lead to the activation of Rho kinase and protein kinase C (PKC), which results in Ca²⁺ sensitization by phosphorylating and inhibiting MLC phosphatase. DAG, diacylglycerol; P, phosphate; and PLC, phospholipase C.

Figure 5

Moxonidine-induced inhibition of atherosclerosis. Moxonidine decreases the expression of inflammatory genes, inhibits the oxidation of LDL, and enhances VSMC migration. VSMCs then migrate to a location that could facilitate both oxidized LDL uptake via the LDL receptor and its efflux back to circulation via the ABCG1 transporter for detoxification by the liver. ↓, decrease; ABCG1, ATP binding cassette subfamily G member 1; CCL2, chemokine ligand 2 (also known as monocyte chemoattractant protein-1); EC, endothelial cell; IL, interleukin; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; Mox, moxonidine; TNF-α, tumor necrosis factor-α; and VSMC, vascular smooth muscle cell. This figure is from Wang et al. with permission [76].

Figure 6

Production of oxidants by norepinephrine metabolism.