**2. Aging endothelium—mechanisms of endothelial senescence**

Endothelial cell senescence is a physiological process of irreversible cell cycle arrest to which various biological stress conditions such as, telomere shortening, DNA damage, reactive oxygen species (ROS) production and mitochondrial dysfunction contribute. Cellular senescence is a process in which vascular cells stop dividing and undergo characteristic phenotypic changes, such as profound changes in chromatin and secretome [5]. Vascular endothelial cell senescence has been found to play a key role in vascular aging, leading to the initiation, progression and development of vascular atherosclerosis [6]. Aging vascular endothelial cells typically become flatter and enlarged with increasingly polypoid nuclei. These changes are accompanied by modulation of cytoskeletal integrity, angiogenesis, cell proliferation and migration [7]. Aging endothelial cells exhibit decreased production of endothelial nitric oxide (NO), increased release of endothelin-1 (ET-1), increased inflammation and cell apoptosis [7]. Senescence of endothelial cells thus induces structural and functional changes in blood vessels, exacerbating thrombosis, inflammation and atherosclerosis with impaired vascular tone, angiogenesis and vascular integrity, which contributes to the development and progression of atherosclerosis [8]. However, the molecular mechanisms of vascular endothelial cell aging and their relationship to underlying pathophysiological changes are not yet fully understood. In this chapter, the role of genetic factors affecting the mechanisms of endothelial cell senescence in the process of vascular aging and the development of atherosclerosis will be discussed.

Cellular senescence is a physiological or pathological process that occurs throughout life [9]. Under physiological conditions, cellular senescence is involved in embryonic tissue development, tissue repair, and tumor suppression responses [9]. However, the accumulation of senescent cells can lead to loss of replicative capacity, cell apoptosis, unfavorable structural changes and the associated development of atherosclerosis [9]. Cellular senescence is usually associated with aging and

### *Genetic Markers of Endothelial Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.109272*

age-related disorders. In human coronary arteries, endothelial cells with increased β-galactosidase activity associated with enhanced senescence are observed during aging, suggesting that aging is also associated with decreased endothelial cell regeneration and endothelial cell senescence, which is associated with decreased endothelium-dependent arterial relaxation [10] and the development of arterial stiffness [9]. Several studies have found that NO donors reduce arterial stiffness in healthy subjects and in patients with hypertension and hypercholesterolemia [10]. These data support a role for aging vascular endothelial cells in the pathogenesis of arteriosclerosis. However, while few clinical studies have examined the relationship between endothelial aging, arterial stiffness and hypertension, those that have been conducted have shown that aging is closely associated with arterial stiffness and atherosclerosis. For example, data from the Framingham Heart Study showed that older age was significantly associated with higher carotid-femoral pulse wave velocity and mean arterial pressure [11]. Arterial stiffness has been shown to be an independent biomarker of atherosclerotic morbidity and mortality in the general population, in aging individuals, in patients with hypertension and in patients with end-stage renal disease [12]. With aging and the associated arterial stiffness, systolic blood pressure tends to increase while diastolic blood pressure tends to decrease, and this pathophysiological change results in an increase in pulse pressure and pulse wave velocity in the aorta. Indeed, it has also been observed that the prevalence of hypertension, especially isolated systolic hypertension, is increased in the aging population [13]. Increased systolic pressure increases left ventricular afterload with an associated increase in myocardial oxygen demand. Declining diastolic pressure reduces perfusion of the coronary circulation during diastole. These consequences of arterial stiffness, increased systolic pressure and decreased diastolic pressure further induce left ventricular hypertrophy and subsequent myocardial ischaemia, remodeling and other cardiovascular complications in aging individuals [8].
