Nicotine and vascular dysfunction

Abstract

Cigarette smoking is the single most important risk factor for the development of cardiovascular diseases (CVDs). However, the role of nicotine, the addictive component of all tobacco products, in the development of CVD is incompletely understood. Although increased public awareness of the harms of cigarette smoking has successfully led to a decline in its prevalence, the use of electronic cigarettes (e-cig) or electronic nicotine delivery system has increased dramatically in recent years because of the perception that these products are safe. This review summarizes our current knowledge of the expression and function of the nicotinic acetylcholine receptors in the cardiovascular system and the impact of nicotine exposure on cardiovascular health, with a focus on nicotine-induced vascular dysfunction. Nicotine alters vasoreactivity through endothelium-dependent and/or endothelium-independent mechanisms, leading to clinical manifestations in both cigarette smokers and e-cig users. In addition, nicotine induces vascular remodelling through its effects on proliferation, migration and matrix production of both vascular endothelial and vascular smooth muscle cells. The purpose of this review is to identify critical knowledge gaps regarding the effects of nicotine on the vasculature and to stimulate continued nicotine research.

Keywords: endothelial cells; nAChR; nicotine; vascular dysfunction; vascular smooth muscle cells.

Figure 1.. Nicotinic Acetylcholine Receptors (nAChR).

(A) The nAChR are divided into three major subtypes: muscle-type, heteromeric and homomeric nAChR. The muscle-type nAChR consists of (α1)₂β1δε (adult) or (α1)₂β1δγ (fetal) and is located at the neuromuscular junction, and this receptor is poorly responsive to nicotine. The heteromeric nAChR are composed of five subunits in various combinations of α and β subunits, and the homomeric nAChR are composed of five α subunits (α7 or α9). Ligands (ACh or Nicotine) bind to the α subunits at the subunit interface. (B) The nAChR are ligand-gated cation channels. Upon binding to endogenous ligand ACh or nicotine, the central pore of nAChR opens to allow the flow of cations (Na⁺ and Ca²⁺ into and K⁺ out of the cells). ACh, acetylcholine.

Figure 2.. Nicotine alters vascular reactivity through endothelium-dependent and endothelium-independent mechanisms.

Activation of the endothelium elicits a multitude of pathways with the production of vasoactive substances that travel to the underlying vascular smooth muscle cells (VSMC) to induce vasoconstriction or vasodilation. Nicotine (Nic) has been shown to upregulate the production or release of the vasoconstrictor endothelin-1 (ET-1) and inhibit endothelial production of the vasodilators nitric oxide (NO) and prostacyclin (PGI₂). In VSMC, nicotine promotes VSMC contraction by amplifying its response to norepinephrine (NE), by upregulating ET-1 receptor (ET_A and/or ET_B) expression, and/or by inhibiting ATP-sensitive K⁺ channels. Up- and down-regulation by nicotine are indicated by ↑ and ↓, respectively. ADMA, asymmetric dimethylarginine (the endogenous eNOS inhibitor); BH4, tetrahydrobiopterin (an essential cofactor for eNOS); COX, cyclooxygenase; eNOS, endothelial nitric oxide synthase; GTPCH1, GTP cyclohydrolase 1 (the rate-limiting enzyme for BH4 production); PGH₂, prostaglandin H₂.

Figure 3.. Nicotine and Vascular Remodeling.

Acute nicotine exposure at concentrations similar to those found in human smokers promotes angiogenesis, whereas chronic exposure to nicotine blunts its proangiogenic response. Both acute and chronic nicotine exposure lead to fibroblast proliferation, extracellular matrix deposition, and vascular smooth muscle cell (VSMC) proliferation and migration. In addition, chronic nicotine exposure is associated with elastin fragmentation and neointima formation.