Endothelial dysfunction and aging: An update

Abstract

Aging is an important risk factor for the development of many cardiovascular diseases as atherosclerosis and hypertension with a common underlying circumstance: the progressive decline of endothelial function. Vascular endothelial dysfunction occurs during the human aging process and is accompanied by deterioration in the balance between vasodilator and vasoconstriction substances produced by the endothelium. This imbalance is mainly characterized by a progressive reduction of the bioavailability of nitric oxide (NO) and an increase in the production of cyclooxygenase (COX)-derived vasoconstrictor factors. Both circumstances are in turn related to an increased production of reactive oxygen and nitrogen species.

The aim of this review is to describe the pathophysiological mechanisms involved in the endothelial function declination that accompanies the multifactorial aging process, including alterations related to oxidative stress and pro-inflammatory cytokines, senescence of endothelial cells and genetic factors.

Introduction

Aging is one of the main risk factors for the development of cardiovascular diseases, and it is associated with complex structural and functional alterations in the vasculature (Lundberg and Crow, 1999, Ferrari et al., 2003, Yildiz, 2007). Dysfunction of both the vascular endothelium and smooth muscle cells appears to occur as age progresses. Transduction pathways and communication between endothelial cells and smooth muscle cells are also altered (Yildiz, 2007). The main changes in vascular smooth muscle cells shown in aged arteries are related to an increased migration and/or proliferation of these cells, changes in their proliferative and apoptotic behavior, response to growth factors (e.g. transforming growth factor-b1), a reduced density of Ca²⁺-activated K⁺ channels in coronary smooth muscle and an increased response to endothelial constrictor factors and K⁺ (Toro et al., 2002, Ferrari et al., 2003).

As mentioned above, vascular endothelial dysfunction occurs during the human aging process and is an independent risk factor for the development of atherosclerosis and hypertension. This “dysfunction” favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis and it is considered as a crucial event in the development of many vasculopathies. Hence, endothelial dysfunction has become a hallmark, and indeed a predictor of cardiovascular disease. Healthy endothelial function is primarily regulated by several factors including endothelium-dependent relaxing factors (EDRFs), endothelium-dependent contracting factors (EDCFs) and endothelium-dependent hyperpolarizing factor (EDHF). The aging process is accompanied by deterioration in the balance between vasodilator and vasoconstriction substances produced by the endothelium (Ferrari et al., 2003, Matz and Andriantsitohaina, 2003, Brandes et al., 2005). This imbalance is mainly characterized by a progressive reduction of the bioavailability of nitric oxide (NO) and an increase in the production of cyclooxygenase (COX)-derived vasoconstrictor factors (Ferrari et al., 2003, Matz and Andriantsitohaina, 2003, Brandes et al., 2005). Both circumstances are in turn related to an increased production of reactive oxygen species (ROS) (e.g. superoxide ion (O₂⁻), hydrogen peroxide (H₂O₂), and peroxyl radical (OH)), and reactive nitrogen species (RNS) (e.g. NO and peroxynitrite (ONOO⁻) (Brandes et al., 2005). Other factors that may contribute to the deterioration of endothelial function in aging are the EDHF, the endothelin-1 and the senescence of endothelial cells (Brandes et al., 2005, Vanhoutte, 2009). Overall, these age-related alterations may be also affected by an increased expression of pro-inflammatory cytokines that accompanies the process of senescence and that frequently lead to the alteration of the expression and/or activity of certain enzymes (Ungvari et al., 2004, Minamino and Komuro, 2007).

The presence of endothelial dysfunction in old people is associated not only with cardiovascular diseases such as atherosclerosis, coronary artery disease or cardiovascular disorders resulting from diabetes mellitus and arterial hypertension (Wallace et al., 2007), but also with diseases related with aging as the erectile dysfunction (Burnett, 2006), renal dysfunction (Csiszar et al., 2007a), Alzheimer disease (Price et al., 2004), circadian cycle alterations (Kunieda et al., 2008), osteoporosis (Sanada et al., 2004) and retinopathy (Coleman et al., 2008).

The knowledge of the molecular mechanisms involved in vascular dysfunction associated to aging may contribute to understand the extent and nature of these alterations and to potentially develop strategies to attenuate the effect of aging in the vasculature, preserve the quality of life, and alleviate cardiovascular diseases in an increasing older population. Our review is an attempt to summarize and update the major mechanisms participating in the alteration of vascular and endothelial function that accompanies the multifactorial aging process, with special emphasis in age-related endothelial dysfunction. Throughout this review, we describe recent findings in the elderly related to alterations in oxidative stress and pro-inflammatory cytokines, senescence of endothelial cells and genetic factors.