Aging is one of the major challenges facing developed societies in the current century. In the United States today there are 35 million people 65 years of age or older, and their number will double by the year 2030 . Thus, age-related problems will increasingly engage all levels of social organization: individual citizens, health care providers, and government authorities fixing priorities for funding allocation are called to tackle different facets of the aging mosaic. Aging classically reminds us of the Janus myths, with a favorable side represented by the gain in individual life expectancy, and a second one with its weight of increased susceptibility to disease and disability. Widening knowledge about age-related disease mechanisms and clinical consequences may help improve both quality of life for elder subjects and global community health.
Aging is a major risk factor for congestive heart failure, stroke, coronary events, and peripheral arterial obstructive disease. A number of age-associated changes in cardiovascular structure and function are implicated in the increased risk for cardiovascular disease in older persons. An increased intimal-medial thickness (IMT) and wall stiffness of large arteries, as well as endothelial dysfunction, are recognized so far as the best established fingerprints of vascular aging in apparently otherwise healthy older persons. Recent advances in vascular biology have pointed out age-associated cellular, enzymatic, and molecular mechanisms that underlie vascular remodeling . The activation of stress-responsive genes is thought yield elevated levels or activity of growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor-b (TGF-b), and angiotensin II, proteolytic enzymes (metalloproteases,
MMPs), adhesion molecules, and inflammatory cytokines (ICAM-1 and interleukin-6, IL-6). Such a "molecular remodeling" provides the metabolic milieu for smooth muscle cell (SMC) proliferation, migration, and apoptosis, as well as for synthesis of extracellular matrix proteins (i.e., fibrosis), disruption of basal membrane and elastin, and increased endothelial permeability.
The concept of endothelial senescence represents a recent breakthrough for understanding age-related and atherosclerotic vascular diseases and also exhibits great potential from a diagnostic point of view, for the follow-up of disease progression/regression, and possibly for therapeutic interventions . Endothelial senescence can be identified in cell cultures or in bioptic samples by histochemistry (b-galactosidase staining) and is characterized by the suppression of telomerase activity. Telomere length is a marker of cellular turnover and is inversely associated with age, atherosclerotic grade, and pulse pressure . Loss of telomere function was recently shown to induce endothelial dysfunction in vascular endothelial cells, whereas inhibition of telomere shortening suppresses the age-associated dysfunction in these cells . Very recently, endothelial progenitor cells (PECs) deriving from bone marrow have been identified in peripheral blood, and it has been proposed that circulating PECs normally repair and rejuvenate vascular endothelium; thus, their exhaustion due to a persisting challenge such as atherosclerosis, chronic inflammatory processes, or aging could hamper vascular repair and facilitate progression of vascular disease independent of the major risk factors .
Two key theoretical questions are open, with significant implications for vascular aging. The first one confronts the programmatic theory of aging, stating that aging is an inherent genetic process, with the stochastic theory, suggesting that it represents the result of random environmental damage ; the latter relates to the overlap between aging and atherosclerosis. Age-associated changes in vascular structure and function and atherosclerosis are intertwined and interdependent. In fact, the prevalence of risk factors for atherosclerotic disease such as high blood pressure, obesity, insulin resistance, and physical inactivity increases with age, and vascular inflammation, endothelial dysfunction, and oxidative stress are the common end pathways underlying vascular disease. To date, evidence is mounting that subclinical vascular disease in older persons represents specific aspects of vascular aging and is not synonymous with low-grade atherosclerosis . Rather, aging increases susceptibility to atherosclerosis, facilitating an imbalance between protective and insulting vascular factors for a given athero-genic load, whereas a different burden from modifiable risk factors could accelerate or delay the impact of age, resulting in the well-known possible discrepancy between biological and chronological age.
The question also arises as to what extent different vascular beds may share similar mechanisms of disease, and knowledge gained from studying large arteries and cell cultures can be extrapolated to human microvasculature in vivo. Despite deep differences between regional circulations depending on the specific organ function, the basic pattern of response of SMCs and endothelial cells to inflammatory and oxidative injury seems to be quite uniform throughout the vascular tree, which allows us to foresee an extension to peripheral microvasculature of modern discoveries about vascular senescence.
Figure 1 Diagram of vascular anatomy in plantar skin. From Conrad, M. C. Functional Anatomy of the Circulation of Lower Extremities. Copyright © 1971 by Year Book Medical Publishers, Inc., Chicago.
Skin is a complex organ, with a wide surface area of about 2 square meters, which consists of two layers. The outer one, the epidermis, is a waterproof layer of keratiniz-ing stratified squamous epithelium. The inner layer, dermis or corium, is connective tissue that supports the epidermis and hosts the microvasculature.
Skin microcirculation guarantees three main functions : skin tissue nutrition, heat exchange for thermoregulation, and blood flow redistribution during stress. Skin blood flow spans throughout an extremely wide range (in nonacral skin, from 1.0mL/min per 100 g, needed to meet the relatively low intrinsic tissue metabolic demand, to 8.0mL/min per 100 g, and in acral regions from 0.2 to 50mL/min per 100 g). Under extreme thermal stress, skin blood flow can account for up to 50 percent of total cardiac output. Such a functional reserve is made possible by a fine control of cutaneous vascular resistance, capable of large dynamic changes in response to local, mechanical, and humoral factors, as well as to the autonomic nervous signaling. A peculiar microvascular architecture provides the anatomic substrate for this functional dynamics.
Microcirculatory bed in human dermis is organized in four plexuses (Figure 1): deep, intermediate, subsuperficial, and superficial (the so-called papillary plexus). These vessels tend to be arranged parallel to the skin surface, with the exception of, first, the capillary loops that are arranged perpendicular to the cutaneous surface and, second, the arterioles and venules which come from the deep to the superficial plexus. Skin microvessels have relatively thick walls that protect them against the shearing stresses to which the skin is exposed. The greater thickness of their walls is due to a membrane basement layer in which smooth muscle cells, pericytes, collagen, and elastin are embedded. Three to four branching orders of arterioles (from order 0, corresponding to capillaries, to order 4, assigned to the largest arterioles, with a diameter of 100 to 150 pm), are reported in the skin microvascular bed. Arterioles show spontaneous diameter oscillations, referred to as vasomo-tion, with a specific range of frequencies that vary according to the vessel order, as demonstrated by the work of Colantuoni, Bertuglia, and others. As shown by Griffith and others, arteriolar diameter oscillations may modify local blood flow distribution. In particular, they yield a reduced resistance in microvascular networks compared with those with steady conditions, and ensure an intermittent but adequate flow to the tissue in presence of a decreased blood flow supply .
A special feature of cutaneous microvasculature is the presence of numerous arteriovenous anastomoses (AV), which are coiled vessels with an average lumen of 35 pm, connecting arterioles and venules in the acral skin. They are present mainly in the hands, feet, ears, and nail beds, but have not been found in the skin of the forearm or the calf. Their function is to allow the blood flow directly from the arterioles to the venules of the deep plexus, bypassing the high-resistance arterioles and capillaries of the more superficial plexus. Having a dense innervation and a thick layer of smooth muscle cells in their walls, they play a major role in determining the neurally mediated changes in arteriolar tone and microvascular resistance that occur in response to thermal stimuli.
Control Mechanisms of the Skin Microcirculatory Perfusion
The fine tuning of skin microvascular resistance and blood flow distribution is obtained through the dynamic interaction of sympathetic vasoconstriction, pressure-dependent vasoconstriction, flow-dependent endothelium-mediated vasodilation, metabolic vasodilation, and spontaneous myogenic activity . At a given time, not all skin microvascular units are open and perfused. The functional recruitment of previously inactive units represents a further mechanism for increasing capillary perfusion during exercise or passive thermal stress. The different control mechanisms modulate diameter oscillations of the arteri-oles, that is, vasomotion, which results, as shown by Bertuglia and Colantuoni, in blood flow oscillations, the so-called flowmotion. By power spectral analysis of Laser Doppler perfusion monitoring signals, a low-frequency component of flowmotion oscillating at 0.1 Hz has been unequivocally associated to the sympathetic activity . Thus, the well-known age-related increase in basal sympathetic activity and reduced tonic baroreflex sympathoinhibi-tion may have an impact on skin microcirculatory control and be revealed by the analysis of variability component on laser-Doppler recordings.
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