Sci. Aging Knowl. Environ., 18 February 2004
Vol. 2004, Issue 7, p. pe7
[DOI: 10.1126/sageke.2004.7.pe7]

PERSPECTIVES

Impaired Angiogenesis in the Aged

May J. Reed, and Jay M. Edelberg

May J. Reed is in the Department of Medicine in the Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98104, USA. E-mail: mjr{at}u.washington.edu. Jay M. Edelberg is in the Departments of Medicine and Cell and Developmental Biology at Weill Medical College of Cornell University, New York, NY 10021, USA. E-mail: jme2002{at}med.cornell.edu

http://sageke.sciencemag.org/cgi/content/full/2004/7/pe7

Key Words: vasodilation • coagulation • growth factors • extracellular matrix • wound healing • atherosclerosis

Introduction

Angiogenesis, the development of new microvessels from preexisting vasculature, is delayed and altered with age (1-4). Tissues from aged individuals display a substantially lower capillary density than do tissues from non-aged counterparts (Fig. 1), and the neovascular response in aged tissues is delayed by approximately 40% as compared to the response of tissues from younger individuals. As illustrated in Fig. 2, both cellular and extracellular components of the angiogenic response are altered during aging. The subsequent impairment of angiogenesis is detrimental to the revascularization of ischemic (hypoxic) organs and to the repair of injured tissues. Conversely, the decline in angiogenesis with age might slow tumor growth, thereby providing partial protection from the rapid development of clinically significant cancers in older people.



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Fig. 1. Angiogenesis is impaired during aging. An immunofluorescent stain for laminin, a component of the basement membrane of small vessels, illustrates the fact that decreased vessel density (arrows) accompanies the delay in angiogenesis in aged mouse tissues relative to young tissues. Scale bar, 100 µm.

 


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Fig. 2. Alterations in the angiogenic response that occur during aging. These changes include (1) impaired vasodilation, (2) enhanced thrombotic potential, (3) deficits in growth factor expression and signal transduction, (4) inhibited endothelial cell (EC) migration, (5) alterations in matrix synthesis and turnover, and (6) decreased proliferation of mature and progenitor endothelial cells.

 
This Perspective discusses the molecular and cellular events that mediate changes in the behavior of the endothelial cells (which line the microvasculature) and lead to impaired angiogenesis in normal aging, as well as the clinical significance of these changes to wound repair, cardiovascular disease, and cancer. However, it is important to note that the coexistence of hypertension, diabetes, smoking, and hypercholesterolemia exacerbates the inherent effects of aging that are detrimental to angiogenesis (5-7).

Models for the Study of Aging and Angiogenesis

The study of angiogenesis in tissues of aged humans remains a significant challenge. In addition to a high prevalence of diseases that affect vascular function (such as diabetes and atherosclerosis), older individuals exhibit greater variations in nutritional status and exposure to prescription and over-the-counter drugs than do their younger counterparts. Moreover, even a population that is matched for the presence of disease and environmental insults will have inherent differences in the rate at which their organs and tissues age, resulting in increased variability among individuals in a given birth cohort (see, for example, Walston Perspective). Accordingly, "old-old" humans (those over 85 years of age) are more difficult to study than "young-old" (65 to 74 years) and "middle-old" (75 to 84 years) humans. Cells derived from young donors and "aged" in culture, via serial passage, have provided an alternative method to examine the changes in endothelial cell behavior that are associated with the aged phenotype (8, 9) (see "More Than a Sum of Our Cells").

In contrast to humans, animals demonstrate less individual variability as they age. Studies primarily in rodent models (mice and rats 22 to 30 months of age) and rabbits (48 to 60 months) have yielded important and largely reproducible information on age-related changes in angiogenesis (1-4, 10, 11). The point at which an animal is defined as "aged" is dependent on the strain (hybrids often live longer) and environmental factors such as diet [calorie-restricted mice and rats live longer than ad lib-fed rodents (see Masoro Subfield History)]. It is generally accepted that an animal is "aged" at the point in its life span at which 50% of its age-matched cohorts have expired.

Pathogenesis of Impaired Angiogenesis in Aging

Vasodilation

In the non-aged vasculature, imbalances in circulatory supply and demand are initially counteracted by vasodilation, during which blood vessels relax and their diameter increases, thereby enhancing tissue perfusion. In contrast, aged vessels have an impaired vasodilatory response that inhibits the passage of blood to ischemic tissues. Although the age-related decrement in vessel relaxation does not occur uniformly in all organs, it is generally accepted that older persons have substantially decreased vasodilation, as compared to younger individuals with otherwise matched clinical characteristics. Factors contributing to impaired vasodilation include a decrease in nitric oxide production (see "Shear Benefits" and "NO-aspirin, No Atherosclerosis") and an age-associated increase in vasoconstriction induced, in part, by the potent peptide hormone endothelin-1 (7, 12, 13-16).

Coagulation

Changes in the intrinsic coagulability of blood might also contribute to impaired angiogenesis in aging. Large-scale population-based studies have demonstrated that aged vasculature is associated with higher than normal serum concentrations of coagulation enzymes and markers that reflect the turnover of fibrin, the primary insoluble component of blood clots. Specific assays have revealed that the following substances are present in increased amounts in aged individuals: (i) activated clotting factors; (ii) plasminogen activator inhibitor-1 (a fibrinolytic enzyme inhibitor associated with thrombosis, which is the formation of an aggregate of fibrin, platelets, and other components that can obstruct blood vessels); and (iii) by-products of fibrin breakdown such as d-dimers. Concomitant decreases in the activity of coagulation inhibitors (for example, activated protein C and antithrombin III) with age might further predispose older individuals to coronary and cerebrovascular thrombotic events (17-22). In addition, age-related imbalances in the activity of enzymes in the coagulation and fibrinolytic pathways might inhibit the cleavage, and subsequent activation, of growth factors and matrix metalloproteinases (MMPs) that facilitate endothelial cell function during angiogenesis (23, 24).

Growth factors

It is generally accepted that deficient expression and function of growth factors, including vascular endothelial growth factor (VEGF) (2, 25), platelet-derived growth factor (PDGF) (26), basic fibroblast growth factor (8), and transforming growth factor-{beta} (TGF-{beta}) (27-29), contribute to deficits in endothelial function (proliferation and migration), thereby leading to impaired angiogenesis in aged tissues. The lack of angiogenic growth factors can be exacerbated by delays in the influx and function of inflammatory cells, which augment the delivery of cytokines (a class of mediators that are produced by immune cells and modulate the effects of growth factors) (3, 4). Restoration of angiogenic growth factors through protein delivery or induced expression has been shown to promote angiogenesis in aged animal models (2, 10, 30). It is probable that physiological decreases in the concentrations of steroid hormones (for example, estrogen and testosterone) as a result of menopause and "normal aging" contribute, both directly and indirectly, to subsequent deficits in the synthesis and function of angiogenic growth factors (28, 31).

VEGF. The expression of VEGF, a critical component of both physiological and pathophysiological angiogenesis (32), is diminished in the basal state and after injury of the tissues of aged animals (2-4). Decreased synthesis appears to result from reduced hypoxia-induced transcriptional activation of the VEGF gene in aged rabbits (25) and might increase the severity of peripheral vascular disease (2) and cutaneous wounds (3). In addition, impaired VEGF expression has been associated with decreased capillary density and corresponding loss of renal function in the aging kidney (33). In contrast, VEGF activity is enhanced in the vitreous body of the eye (the transparent substance in the inner region of the eyeball) of aged humans in the neovascularized form of macular degeneration. In this pathological condition, increased VEGF activity is a result of significant deficits in the concentration of pigment epithelium-derived factor (PEDF, also known as EPC-1), a potent inhibitor of angiogenesis (34).

PDGF. Whereas VEGF plays a primary role in angiogenesis of the peripheral vasculature that perfuses the extremities, PDGF pathways regulate neovascularization of the myocardium. Previous studies have demonstrated that angiogenesis in cardiac microvascular endothelial cells is governed by PDGF-mediated communication with surrounding cardiac muscle cells. In the aged rodent heart, PDGF expression is diminished, partly as a result of deficient expression by cardiac microvascular endothelial cells and endothelial progenitor cells (35). Restoration of PDGF pathways specifically reverses the age-associated decline in cardiac neovascularization, promoting microvascular growth into transplanted heart tissue and increasing vascular density in the endogenous heart (see Edelberg Perspective). Indeed, delivery of PDGF at supraphysiological concentrations in aged rats is cardioprotective, reducing the extent of myocardial injury after coronary occlusion (30).

Fibroblast growth factor (FGF). Age-related alterations in vascular growth factor pathways are also linked to deficits in FGF (3, 8). Concentrations of FGF-2 decrease more rapidly with age than those of PDGF (36). Wounds in aged mice contain substantially less FGF-2 than wounds from young animals (3). Lower concentrations of FGF in aged tissues can impair angiogenesis directly or can do so indirectly through PDGF-dependent pathways (37).

Aging and impaired growth-factor responses. Although the replacement of deficient angiogenic factors enhances vessel formation in aged animals, it is important to note that the response of aged tissues is usually less robust than that attained by growth factor stimulation of young tissues (3, 10). Mechanisms for the depressed response that occurs during aging include age-related defects in receptor-mediated signal transduction and excess activation of inhibitory cascades. Moreover, shifts in pathways that govern apoptosis also occur. Whereas the cytokine tumor necrosis factor-{alpha} (TNF-{alpha}) normally mediates induction of PDGF signaling and the subsequent enhancement of angiogenesis in endothelial cells, with aging there are increases in certain TNF receptor-associated proapoptic cascades. These changes, coupled with increased systemic concentrations of TNF-{alpha}, favor apoptosis in aged endothelial cells and the concurrent inhibition of angiogenesis (38-42).

The Extracellular Matrix and Angiogenesis in Aging

Angiogenesis requires a protein scaffold for endothelial cells to attach to, migrate on, and invade. Proteins of the extracellular matrix, such as collagens and thrombospondins, support endothelial cell networks and modulate their behavior. Cellular attachment to these proteins is mediated largely by the integrins, a sizeable family of heterodimeric receptors that serve as the transmembrane bridge between extracellular molecules and intracellular signaling pathways. Proteolytic degradation of matrix components during migration and invasion is regulated primarily by MMPs that are secreted by both endothelial and supporting cells. The latter include mural cells (cells that are adjacent to endothelial cells in the microvasculature, such as pericytes and smooth muscle cells) and fibroblasts.

Matrix proteins

Proteins of the extracellular matrix play regulatory roles (for example, thrombospondins, which influence processes such as cell adhesion and proliferation) as well as structural roles (for example, collagens, fibronectin, and laminin). In most aged tissues (the heart is a notable exception), there is a decrease in the amount of fibrillar collagen (the primary structural protein) as a result of both reduced production and increased degradation. With its physical properties also altered, the collagen assumes a disorganized random orientation that may fail to support endothelial migration (43). Fibronectin is a large extracellular protein that functions to regulate inflammation and cell adhesion by providing a provisional matrix, along with collagen III, for cell migration during the early phases of tissue repair and angiogenesis. Although aged cells have been associated with an increase in fibronectin synthesis in culture, studies of aged tissues and wounds in aged animals have shown decreased fibronectin expression in conjunction with reduced levels of collagen (43). Less is known about the age-related changes that occur in the deposition of basement membrane proteins such as laminin and type IV collagen. Excess deposition of these proteins is found in the pathological states of diabetes and atherosclerosis, but their expression is similar in the microvasculature during angiogenesis in healthy young and aged tissues (4).

In contrast to traditional structural matrix proteins, "matricellular" proteins [such as tenascin, SPARC (secreted protein acidic and rich in cysteine; also known as BM-40 or osteonectin), thrombospondin-1 (TSP-1), and thrombospondin-2 (TSP-2)] primarily modulate endothelial cell behavior (44). Accordingly, matricellular proteins provide an additional point of regulation in the local balance among pro-angiogenic (for example, VEGF) and anti-angiogenic (for example, angiostatin and PEDF) (34) factors that determine whether a blood vessel will grow. It is now generally accepted that the expression of TSPs (inhibitors of angiogenesis) is increased in healthy aged tissues (4, 33, 45) and might contribute to delayed angiogenesis in aging. SPARC is a multifunctional protein that regulates tissue remodeling and endothelial cell proliferation; whether its expression and function undergo age-related changes is controversial. Interestingly, young SPARC-null mice exhibit increased VEGF expression and enhanced angiogenic invasion into sponge implants relative to wild-type mice. Moreover, fibroblasts derived from the SPARC-null mice secrete more VEGF than fibroblasts from wild-type mice, suggesting that the presence of SPARC inhibits VEFG production (46). However, the aged SPARC-null mouse has an impaired angiogenic response into sponge implants that is identical to that of its aged wild-type counterpart. The loss of a distinctive phenotype in aged SPARC-null mice is associated with deficits in collagen quality and VEGF availability, changes that are pervasive in aged tissues and occurred in both groups of aged mice independent of their genotype (47).

Integrins

Little is known about changes in integrin expression and function with aging. A lack of available integrins at the cell surface has been noted in fibroblasts aged in vitro (48). However, recent studies have found that age-related declines in integrin-mediated functions, such as cellular attachment and migration, are probably caused by defects in communication between the integrin complex and intracellular signaling pathways that coordinate the actin cytoskeleton (49). In support of an age-related decline in integrin function (but not expression) are data that show significantly increased amounts of alpha integrin proteins in the myocardium of aged mice (50) (for a discussion of integrin proteins and aging in Drosophila, see Torgler Perspective).

MMPs

The synthesis and activation of MMPs are controlled by several mechanisms, including self-cleavage, growth factor stimulation, exposure to the extracellular matrix, changes in pH, and the clotting/fibrinolytic cascades described above (51). Among MMPs, the expression of collagenases (MMP-1 and MMP-13), stromelysins (MMP-3), gelatinases (MMP-2 and MMP-9), and membrane-type MMPs contribute substantially to angiogenic activity (9, 24). Collagenases degrade intact collagen, and gelatinases cleave previously denatured collagen (gelatin). The membrane-type MMPs activate pro-MMP-2 and mediate pericellular proteolytic activity to support endothelial cell migration.

The expression and activity of MMPs in the aging vasculature are dysregulated. Increased expression of MMP-2 is associated with thickening of the inner layer of blood vessels in the aging rat (52) and age-related aortic remodeling (53), suggesting that enhanced matrix degradation contributes to the vascular dysfunction of aging. Conversely, an age-related decrease in net MMP activity results in reduced migration of aged microvascular endothelial cells on collagen (9). Aged microvascular endothelial cells in three-dimensional collagen gels (a culture model that is more reflective of conditions in vivo than are standard culture conditions) show reduced expression of MMPs and enhanced expression of their endogenous inhibitors, the tissue inhibitors of metalloproteinases, which prevent the formation of capillary-like networks (54). Thus, tissue-specific dysregulation of MMPs, resulting in both excess and deficient activity, is a key factor in age-related vascular pathology and impaired angiogenesis.

Clinical Consequences of Impaired Angiogenesis in Aging

Wound healing

Wound healing has traditionally been divided into three different phases: (i) inflammation; (ii) cell proliferation and granulation tissue formation (during which provisional matrix is deposited and angiogenesis begins); and (iii) tissue remodeling (55). Although it is generally accepted that wound healing is altered in aged individuals (56), whether the alterations represent a slowing of each of the stages or reflect true impairments (that is, the presence of new events and/or the absence of events that are present during wound healing in young individuals) is still debated.

In the unwounded state, there are fewer capillaries in aged skin and other tissues as compared to younger tissues (41, 56). The density and function of nerves and fibroblasts are also diminished as a result of decreased proliferation and possibly increased apoptosis. Whether there are changes with age in the mural cell population (smooth muscle cells and pericytes that are associated with and stabilize the walls of microvessels) is debated (4). Smooth muscle cells obtained from large vessels and arterioles of aged rats do not demonstrate global decreases in proliferation and function in vitro. Indeed, preservation of the replicative and migratory responses in these cell types might predispose the aged vasculature to atherosclerotic changes (57). After injury, angiogenesis occurs during the deposition of granulation tissue in the wound bed. The highly vascularized area subsequently promotes the migration of keratinocytes and fibroblasts, cells that are critical for tissue integrity and remodeling. Accordingly, it is generally accepted that delayed angiogenesis, attributed to decreases in the proliferation and migration of endothelial cells, contributes to slowed wound healing in aged tissue (3, 56). Other age-related defects in endothelial cell behavior during wound repair include increased adhesion to leukocytes, enhanced response to TNF-{alpha}, and greater production of the cytokine interleukin-1 (43, 56). Angiogenesis during repair of aged tissues is also accompanied by reduced concentrations of angiogenic factors such as VEGF, FGF, and TGF-{beta}1 (2-4, 27-29), less collagen deposition, a deficient inflammatory response, and an increase in TSP-2 concentration (3, 4, 45).

Replacement of deficient angiogenic growth factors such as FGF and VEGF improves the migration and proliferation of aged endothelial cells and increases capillary density in aged tissues (2, 10). The extrapolation to enhanced wound repair, as a direct result of increased neovascularization (as opposed to the numerous other changes induced by the application of these factors), remains to be proven. Indeed, in animal models, treatment with an inhibitor of angiogenesis has inconsistent effects on cutaneous wound repair (58, 59). The contribution of angiogenesis to wound healing might be tissue-specific; a lack of newly formed vessels has been shown to be detrimental to repair after intestinal surgery (60). In addition, it is important to note that a limitation on capillary growth that is not detrimental to healing in a young animal might have significant consequences for an aged animal. Whether or not promotion of angiogenesis directly benefits tissue repair, concerns regarding absorption into the systemic circulation have necessitated that therapeutic developments focus on effective interventions that are restricted to the area of the wound bed.

Cardiovascular disease

Ischemic cardiovascular disease is the leading cause of death in Americans over age 65 (61). Even subclinical cardiovascular disease is associated with a decreased likelihood of successful aging (62). Aged patients also have greater morbidity after myocardial infarction, which is consistent with the age-related changes in the vascular system that predispose older individuals to increased cardiac pathology. The protective role of ischemic preconditioning, in which tissue is exposed to brief periods of low oxygen, resulting in enhanced angiogenesis and subsequent resistance to the effects of prolonged hypoxia, is depressed in the aged heart (63, 64). This is manifested in many aged humans by a lack of pre-infect angina (chest pain that serves as a warning that the heart is receiving inadequate oxygen, thereby providing an element of myocardial protection) (65). In addition, analyses of coronary angiographs have shown that subgroups of older patients with diabetes demonstrate decreased collateral circulation (the growth of smaller vessels to compensate for the obstruction of a primary vessel) relative to younger counterparts who are otherwise matched for clinical characteristics (66).

Interventions to enhance angiogenesis in ischemic vascular disease in humans have attained variable results. Some gene therapy studies (involving intramuscular injection of naked DNA encoding VEGF or intracoronary injection of an adenovirus encoding FGF, for example) have suggested the potential clinical utility of pro-angiogenic approaches to cardiovascular disease (67, 68). However, recent data have shown limited benefits of both VEGF and FGF recombinant proteins in the treatment of coronary vascular disease (69). Because these interventions are largely targeted at the aged, clinical trials have also been hampered by concerns that administration of these angiogenic factors in a manner that allows distribution into the circulation might potentiate the growth of previously undetected neoplastic processes. Larger studies are now under way to determine the optimal location and type of delivery (gene or recombinant protein therapy) and which subgroups of patients with vascular disease will achieve the greatest benefit.

Cancer

Although aging is associated with an increased prevalence of cancer (70), tumor growth in older animals tends to be less rapid as compared with the growth of histologically similar tumors in younger animals (71, 72). Indeed, deaths caused by primary malignancies occur with lower frequency in the geriatric population as compared to younger populations (73), resulting in individuals dying with, rather than from, cancer. The biological basis of these associations is multifactorial, including the development of cancers in at-risk populations at younger ages (70), as well as the increased manifestation of cardiovascular diseases as an alternative cause of mortality in older people (61, 62). Primary changes in cellular functions such as decreased mitotic and migratory activity might also contribute to slower tumor growth in older people.

In addition to the above changes, it is probable that impaired angiogenesis in tumors lessens the impact of cancers on the geriatric population. In postmenopausal patients with breast cancer, who were otherwise matched for extent of disease and estrogen receptor status, angiogenesis in tumor beds decreased with advanced age (74). Animal studies have also demonstrated less neovascularization in cancers in aged mice as compared to genetically identical younger counterparts (71, 72). Given the correlation between microvessel density and the prognosis of many tumors, a decrease in vessel density with aging might be of benefit in this clinical context (75). It is possible that many of the changes that occur in aged tissues, in particular diminished concentrations of steroid hormones, growth factors, and other mitogens that enhance angiogenesis, arose as a protective response against the increased incidence of tumors with aging (31). Whether this will translate into a reduced benefit from the adjuvant use of angiogenesis inhibitors to treat malignancies in the elderly remains to be determined (75).

Therapies for impaired angiogenesis in aging

Aged tissues pose unique challenges to the development of effective therapies to enhance angiogenesis. In addition to the molecular and cellular events that mediate changes in endothelial cell behavior, there are also limited endothelial cell reserves available to respond to an angiogenic stimulus. For example, although cell-based therapy might have a role in enhancing angiogenesis in the future (see Edelberg Perspective), it has recently been shown that the availability and function of stem cells, such as endothelial progenitor cells, declines with increased age (76, 77). At the same time, it is important to note that impaired angiogenesis might confer partial protection against neoplasias in aged tissues. Accordingly, harnessing the full clinical potential of growth factors, stem cells, and gene-based therapies for the treatment of older people will require approaches that promote angiogenesis in a restricted area of tissue. Such targeted interventions would treat ischemia while preserving the potential protective effects of decreased angiogenesis on pathological processes such as tumor formation and growth.


February 18, 2004
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  78. The authors thank E. Sadoun and M. Shaw for their assistance with the manuscript and figures.
Citation: M. J. Reed, J. M. Edelberg, Impaired Angiogenesis in the Aged. Sci. Aging Knowl. Environ. 2004 (7), pe7 (2004).




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