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Vascular fibrosis in aging and hypertension: Molecular mechanisms and clinical implications
Adam Harvey, PhD, Augusto C. Montezano, PhD, Rheure Alves Lopes, MSc, Francisco Rios, PhD, Rhian M. Touyz, MBBCh, PhD
PII: S0828-282X(16)00215-4
DOI: 10.1016/j.cjca.2016.02.070
Reference: CJCA 2058
To appear in: Canadian Journal of Cardiology
Received Date: 10 February 2016
Revised Date: 18 February 2016
Accepted Date: 18 February 2016
Please cite this article as: Harvey A, Montezano AC, Lopes RA, Rios F, Touyz RM, Vascular fibrosis in aging and hypertension: Molecular mechanisms and clinical implications, Canadian Journal of Cardiology (2016), doi: 10.1016/j.cjca.2016.02.070.
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Vascular fibrosis in aging and hypertension: Molecular mechanisms and clinical implications
Adam Harvey PhD, Augusto C Montezano PhD, Rheure Alves Lopes MSc, Francisco Rios PhD,
Rhian M Touyz MBBCh, PhD*.
Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre,
University of Glasgow.
Short title: Fibrosis and vascular aging
Key words: vascular stiffness, collagen, elastin, extracellular matrix,
*To whom correspondence should be addressed:
Rhian M Touyz MD, PhD
Institute of Cardiovascular and Medical Sciences,
BHF Glasgow Cardiovascular Research Centre, University of Glasgow,
126 University Place, Glasgow, G12 8TA,
Phone: + 44 (0)141 330 7775/7774, Fax: + 44 (0)141 330-3360,
Abstract
Aging is the primary risk factor underlying hypertension and incident cardiovascular disease. With ageing the vasculature undergoes structural and functional changes characterised by endothelial dysfunction, wall thickening, reduced distensibility and arterial stiffening. Vascular stiffness results from fibrosis and extracellular matrix remodeling, processes that are associated with aging and amplified by hypertension. Some recently characterised molecular mechanisms underlying these processes include increased expression and activation of matrix metalloproteinases (MMPs), activation of TGFpi/SMAD signaling, upregulation of galectin-3 and activation of pro-inflammatory and pro-fibrotic signaling pathways. These events can be induced by vasoactive agents, such as angiotensin II (Ang II), endothelin-1 (ET-1) and aldosterone, that are increased in the vasculature during aging and hypertension. Complex interplay between the 'aging process' and pro-hypertensive factors results in accelerated vascular remodelling and fibrosis, and increased arterial stiffness, typically observed in hypertension. Because the vascular phenotype in a young hypertensive individual resembles that of an elderly otherwise healthy individual, the notion of 'early' or 'premature' vascular aging is now often used to describe hypertension-associated vascular disease. Here, we review the vascular phenotype in ageing and hypertension focusing on arterial stiffness and vascular remodeling. We also highlight the clinical implications of these processes and discuss some novel molecular mechanisms of fibrosis and extracellular matrix reorganisation.
Vascular stiffness precedes cardiovascular disease and is a biomarker of risk. Vascular alterations associated with aging in normotensive people are observed in younger hypertensive patients and are more pronounced than in normotensives of similar age. Accordingly, these hypertension-associated changes have been defined as 'early vascular aging' (EVA). Processes underlying arterial aging and EVA include fibrosis and remodelling, which are initially adaptive and reversible, but with time, become maladaptive and irreversible leading to target organ damage.
Hypertension is the largest contributor to the global burden of cardiovascular disease. The WHO estimates that the number of adults with high blood pressure will increase from 1 billion to 1.5 billion worldwide by 20201. This increase is related, in part, to the fact that the population is aging. Of all the factors contributing to hypertension, such as genetics, obesity, dyslipidemia, sedentary life style and diabetes, advancing age is the most important risk factor. Both aging and hypertension are associated with structural, mechanical and functional changes of the vasculature, characterised by increased arterial stiffness, reduced elasticity, impaired distensibility, endothelial dysfunction and increased vascular tone. The prevalence of vascular stiffness and high blood pressure increases with age and as such hypertension has been considered as a condition of aging. Arterial stiffening precedes the development of hypertension and both phenomena occur more frequently in the elderly. The relationship between aging, cardiovascular disease and vascular stiffening is further exemplified in patients with progeria (premature aging), who exhibit accelerated vascular aging and often die of cardiovascular disease . Arterial stiffening is caused primarily by excessive fibrosis and reduced elasticity with associated increased collagen deposition, increased elastin fiber fragmentation/degeneration, laminar medial necrosis, calcification and cross-linking of collagen molecules by advanced glycation end-products (AGEs).
Fibrosis is a dynamic process, which initially is an adaptive repair response that is reversible. However, the fibrogenic process is progressive leading to further worsening of arterial stiffness and fibrosis that gradually extends into the neighbouring interstitial space. Fibrosis occurs in both large and small arteries. In large vessels, vascular stiffening leads to hemodynamic damage to peripheral tissues3. Fibrosis and stiffening of the resistance circulation impair endothelial function, increase vasomotor tone, promote vascular rarefaction and alter tissue perfusion. The combination of 'aging' and pro-hypertensive elements, such as activation of the renin-angiotensin-aldosterone system, inflammation, oxidative stress, salt and genetic factors, results in excessive arterial fibrosis and extracellular matrix (ECM) deposition with amplification of aging-related vascular injury and
replace parenchymal tissue thereby leading to tissue fibrosis, scarring and hypertension-associated target organ damage of the heart, kidney and brain.
At the molecular and cellular levels, arterial aging and hypertension-associated vascular changes are characterised by reduced nitric oxide (NO) production, increased generation of reactive oxygen species (ROS) (oxidative stress), activation of transcription factors, induction of 'aging' genes, stimulation of pro-inflammatory and pro-fibrotic signaling pathways, reduced collagen turnover, calcification, vascular smooth muscle cell proliferation and extracellular matrix remodeling. These processes contribute to increased fibrosis, which is further promoted by pro-hypertensive vasoactive agents, such as, angiotensin II (Ang II), endothelin-1 (ET-1) and aldosterone, which stimulate pro-fibrotic signaling cascades including p38MAPK and the TGF-P-SMAD pathway. Activation of galectin-3 and dysregulation of matrix metalloproteinases (MMPs) and tissue inhibitory metalloproteinases (TIMPs) are involved in ECM remodeling and further enhance vascular fibrosis. Many of these events are upregulated with advancing age and in human and experimental hypertension. Here, we review the vascular phenotype in physiological aging and in hypertension, focusing particularly on arterial stiffness and fibrosis.
Aging-associated vascular alterations
With aging, the vasculature undergoes functional, structural and mechanical changes, characterised by endothelial dysfunction, thickening (remodeling) of the vascular wall and increased stiffening respectively (Figure 1). These changes result in a reduced capacity of arteries to adapt to tissue demands and accordingly may lead to ischemic injury. Pre-clinical and clinical studies have clearly demonstrated that with aging there is impaired endothelium-dependent vasorelaxation with an associated increased permeability and vascular inflammation.
Epidemiological, cross-sectional, clinical and post-mortem studies on healthy individuals of variable ages have clearly demonstrated that intimal wall thickening and dilation are noticeable structural
changes that occur in conduit arteries with advanced aging. Findings from non-invasive vascular phenotyping studies in healthy individuals demonstrated that intimal media thickness increases 2-to-3-fold between 20 and 90 years of age4. Studies in aging non-human primates also showed a relationship between intimal thickness in the thoracic aorta and aging. Exact factors causing progressive intimal thickening with aging in otherwise healthy individuals remain elusive, but a number of distinctive changes at the cellular and morphological levels have been identified including fracture of elastin fibres within the tunica media, increased collagen deposition, cellular senescence and dysregulated cell proliferation. Associated with these events is remodeling of the ECM an essential component of the connective tissue surrounding the vascular wall.
The ECM is composed of basic structural elements (collagen and elastin) and more specialised proteins including fibronectin and proteoglycans. The ECM is a dynamic structure and its components are continuously being turned over through highly regulated systems involving activation of matrix metalloproteinases (MMPs) and tissue inhibitory matrix metalloproteinases (TIMPs). Dysregulation of these processes, together with alterations in pro-fibrotic and pro-inflammatory signaling pathways, likely contribute to aging-associated vascular structural changes.
The vascular phenotype in hypertension resembles aging-associated vascular remodeling
The overall vascular phenotype of an individual at any one time depends not only on 'aging' but also on a combination of multiple interacting factors, such as genetic factors, diet, smoking, diabetes, dyslipidemia, oxidative stress and obesity6,7. Moreover in the presence of pro-hypertensive factors, there is acceleration of aging-associated vascular changes that leads to exaggerated vascular injury and arterial stiffening. In susceptible individuals, the interplay between aging and hypertension leads to 'early vascular aging' and arterial stiffness, where the vascular phenotype in young hypertensive individuals resembles that of elderly otherwise healthy individuals (Figure 1).
Arterial stii
Normally conduit arteries distend to accommodate large pressure ejections from the heart during systole to facilitate perfusion to tissues during diastole. This is determined in large part by the elasticity, distensibility and compliance of the arterial system. Loss of elasticity and increased stiffness demand greater force to accommodate blood flow leading to increased systolic blood pressure, increased cardiac work load and consequent cardiac hypertrophy and risk of cardiovascular
events. Aortic stiffness also affects the microcirculation and vice versa , . Aortic wall stiffening causes increased pulse wave velocity (PWV) and premature reflected waves with elevated central hemodynamic load leading to damage of peripheral small arteries9. Remodeling of small arteries in turn leads to increased peripheral vascular and pulse wave reflection, which can further contribute to aortic stiffness10. Arterial stiffness can be assessed by measuring PWV, pulse wave analysis (PWA), ambulatory arterial stiffness (using 24-hour ambulatory blood pressure monitoring) and by evaluating endothelial function (flow-mediated dilation). PWV is the most commonly used approach and measures the speed of the pressure pulse from the heart as it is propagated through the arteries and is calculated by dividing the distance travelled by the time taken to travel the defined distance. Stiffer arteries result in a more rapid travel time and hence a higher PWV. Various approaches can be used to measure PWV including applanation tonometry, oscillometry, Doppler echocardiography or MRI. Although the measurement of PWV is considered as the most simple, non-invasive, robust and reproducible method to determine arterial stiffness11, it is not yet used in routine clinical practice.
Carotid-femoral PWV is a direct measure of aortic stiffness and is now considered the gold standard
for its evaluation in clinical and epidemiological studies .
Arterial stiffness is a natural consequence of advancing age and is accelerated in hypertension. It is also an independent predictive risk factor of cardiovascular events, and as such aortic PWV is now recognised as an important biomarker in the determination of cardiovascular risk. Arterial stiffness has a bidirectional causal relationship with blood pressure because high blood pressure causes arterial wall injury, which promotes stiffening, while arterial stiffening itself is the major cause of
increased systolic blood pressure, especially in the elderly , . Multiple interacting factors at the systemic (blood pressure, hemodynamics), vascular (vascular contraction/dilation, ECM remodeling), cellular (cytoskeletal organisation, inflammatory responses) and molecular levels (oxidative stress, intracellular signaling, mechanotransduction) contribute to arterial stuffness in aging and hypertension. Dysregulation of endothelial cells, vascular smooth muscle cells and adaptive immune responses have also been implicated in arterial aging and vascular damage in hypertension. A detailed discussion of all these mechanisms is beyond the scope of this review and is addressed elsewhere in the present issue of the journal. Here we focus on some molecular and cellular events that contribute to vascular fibrosis and ECM remodeling.
The extracellular matrix and vascular fibrosis in aging and hypertension.
The ECM is an essential component of the connective tissue that surrounds cells. In addition to maintaining cellular and vascular integrity, it plays a fundamental role in cell signaling and regulation of cell-cell interactions. The ECM comprises multiple structural proteins including collagens, elastin, fibronectin, and proteoglycans. Composition of the ECM varies from organ to organ with collagen type I and III representing the predominant isoforms in the vascular ECM14. The absolute and relative quantities of collagens and elastin determine biomechanical properties of vessels, where an elastin deficiency/collagen excess leads to vascular fibrosis and increased stiffness4, 14. In healthy individuals, collagen deposition and turnover are tightly regulated and the ratio of collagen: elastin remains relatively constant. However, an imbalance in these processes leads to excessive ECM protein deposition, particularly collagen and fibronectin, contributing to vascular fibrosis and stiffening in aging and during the development of hypertension14. Collagens are particularly important in these processes because they are the most abundant and stiffest of the ECM proteins. Increased collagen content, destruction of the elastin fiber network, together with a proinflammatory microenvironment contribute to ECM remodeling and increased intimal media thickening and vascular stiffness in small and large arteries in human and experimental hypertension.
Contributing to the pro-fibrotic process is transglutaminase (TG2), which is secreted into the ECM,
where it catalyzes formation of s-(y-glutamyl)lysine isopeptide, in a Ca -dependent manner . TG2 acts as an extracellular scaffold protein as well as a crosslinking enzyme. Numerous ECM proteins are TG2 substrates, such as fibronectin, collagens, and laminin15. Under physiological conditions TG2 regulates fibroblast activity and ECM organisation, with little protein crosslinking. However, in pathological conditions, increased TG2: ECM protein crosslinking and altered TG2 activity cause increased rigidity and stiffening of the vascular wall, processes that may contribute to remodelling in aging and cardiovascular disease. Recent evidence indicates altered TG2 activity and functionality in large arteries of hypertensive rats 16. TG2 dysregulation has also been implicated in small vessel changes and inward remodelling in hypertension16. Fundamental to many of the processes underlying ECM reorganisation and fibrosis in aging and hypertension is activation of MMPs and TIMPs.
Matrix metalloproteinases (MMP) and tissue inhibitory metalloproteinases (TIMP)
ECM proteins, including collagens and elastin, are regulated by MMPs, a family of endopeptidases, which are activated by many factors associated with aging and hypertension, such as pro-inflammatory signaling molecules (cytokines, interleukins), growth factors, vasoactive agents (Ang II, ET-1, aldosterone) and reactive oxygen species (ROS). MMP activity is controlled at three levels:
gene transcription, proenzyme activation and activity inhibition . Signaling pathways involved in
regulating MMP transcription, include p38MAPK, which can enhance or repress MMP expression in
a cell type-dependent manner (Figure 2). Commonly, MMPs are activated at the pericellular space by
other MMPs including MT-MMPs and MMP-3, or by serine proteases like plasmin and chymase.
Activated MMPs degrade collagen, elastin and other ECM proteins resulting in a modified ECM,
often associated with a pro-inflammatory microenvironment that triggers a shift of endothelial and
vascular smooth muscle cells to a more secretory, migratory, proliferative and senescent phenotype,
which contribute to fibrosis, calcification, endothelial dysfunction and increased intimal-media
thickness further impacting on vascular remodeling and arterial stiffness.
The effect that MMPs have on vascular fibrosis in hypertension is not completely elucidated, with
both inhibitory and stimulatory modulation observed . This probably relates to activation of different MMP isoforms and downstream signaling pathways. For instance, MMP-1 overexpression attenuates fibrosis19 while MMP-9 activation potentiates fibrosis and DNA damage20. MMP2 activation leads to stimulation of TGF-P1 signaling, increased vascular smooth muscle cell production of collagens 1, II and III and increased fibronectin secretion, processes that lead to collagen accumulation in the vascular wall. While activation of vascular MMP2 and MMP9 in hypertension is associated with collagen accumulation, activation of MMP8 and MMP13 is
associated with collagen degradation, processes especially important in arterial wall plaques and
21, 22
plaque rupture , . MMP2/9 activation, through TGFP1-SMAD signaling, also induces activation of
myofibroblasts and increased infiltration of monocytes/macrophages leading to oxidative stress,
inflammation and vascular wall injury. Vascular MMP2 and MMP9 are activated by numerous pro-
hypertensive factors, including Ang II, ET-1 and salt as well as mechanical and physical factors,
such as shear stress and pressure. MMP2-7-9-14 are upregulated by aging. MMP-2 activation is
increased in aged rat aorta, leading to increased TGF-P 1 and SMAD activation . Young rats infused
with Ang II exhibit increased MMP2 activation with intimal media thickness and vascular fibrosis,
changes that are typical in old untreated rats . The importance of MMPs in vascular fibrosis in aging and hypertension is further evidenced by MMP inhibitors, such as PD166793, which blunted age-
associated vascular fibrosis and remodelling in experimental models , .
MMPs are normally inhibited by endogenous inhibitors called TIMPs, of which there are multiple
isoforms. Alterations in the balance between ECM MMPs and TIMPs may contribute to the pro-
18, 23
fibrotic phenotype in aging and hypertension , . The four TIMP isoforms, TIMP-1, TIMP-2, TIMP-3 and TIMP-4, are responsible for the inhibition of over 20 MMPs the relationship between MMPs and TIMPs change with age. For instance, increased MMP-2 expression and activity are observed in vessels of old rats and non-human primates when compared to young counterparts5, 26.
ulateZi^aged animalsLWhLhea
J-----O
animals .
Molecular and cellular mechanisms of vascular fibrosis in aging and hypertension TGF-p-SMAD signaling
The transforming growth factor-P (TGF-P) superfamily consists of more than 40 members that share common sequence elements and structural motifs and includes TGF-P, bone morphogenetic proteins
(BMPs) activins, inhibins and growth differentiation factors - . Disruption of the TGF-P pathway has been implicated in arterial aging and vascular fibrosis28-31. Three isoforms TGF-P1, TGF-P2 and TGF-P3 exist, where TGF-P 1 is most frequently upregulated in ECM remodeling and fibrosis and is consequently regarded as an important regulator of the ECM. In the vascular system, TGF-P 1 is expressed in endothelial cells, vascular smooth muscle cells, myofibroblasts and adventitial macrophages. Activation of vascular TGF-P 1 and its downstream signaling effector, SMAD, increase the synthesis of ECM proteins, such as fibronectin, collagens and plasminogen activator inhibitor-1
32, 33
(PAI-1) , . TGF-P reduces collagenase production and stimulates expression of TIMPS, resulting in excessive matrix accumulation, in part due, to inhibition of ECM degradation34. TGF-P signaling predominantly occurs through the cytoplasmic proteins, SMADs, which translocate to the nucleus and act as transcription factors. The SMAD family comprises receptor-activated SMADs (SMAD, 2, 3, 5 and 8), inhibitory SMADs (SMAD6, 7) and common-partner SMADs (SMAD4). SMAD2 and SMAD3 are specific mediators of TGFP /activin pathways while SMAD7 inhibits both BMP and TGF-P/activin signaling. SMAD activation results in increased transcription of many genes involved in ECM formation including fibronectin, procollagens, PAI-1 and connective tissue growth factor
(CTGF) . In vascular smooth muscle cells, overexpression of SMAD7 inhibits TGF-P-induced
fibronectin, collagen and CTGF production . Important non-SMAD pathways implicated in TGF-P pro-fibrotic signaling include ERK, JNK, p38MAPK, and PI3K/Akt36. SMAD translocation to the nucleus can be modulated by Ras-activated ERK1/2, ERK inhibition reduces TGF-P-stimulated
SMAD phosphorylation as well as collagen production, suggesting that ERK activation is necessary
for an optimal response to TGF-P 1 .
Activation of TGF-P 1 and receptor-mediated signaling are increased in the aortic wall with aging and
23 37 38
during development of hypertension . Important in the context of these conditions, Ang II , ,
33 39 35 40
mechanical stress33, 39, ET-1 and ROS40 are all elevated and are known to mediate TGF-P activation with resulting vascular fibrosis. Additionally, MMPs (particularly MMP-2 and -9) enhance release of TGF-P 1, while TGF-P 1 stimulates TIMP resulting in inhibition of ECM degradation which further induces ECM accumulation and vascular remodeling and fibrosis. Ang II can activate the SMAD pathway independently of TGF-P 1 with implications for fibrosis35,41.
Plasminogen activator inhibitor-1 (PAI-1) is a member of the serine protease inhibitor (serpin) gene family and functions as an inhibitor of the serine proteases, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). PAI-1 inhibits fibrinolysis and hence regulates dissolution of fibrin and inhibits degradation of the ECM by reducing plasmin generation. PAI-1 normally maintains tissue homeostasis through regulating the activities of uPA, tPA, plasmin and MMPs. In pathophysiological conditions, PAI-1 upregulation contributes to accumulation of ECM proteins and tissue fibrosis by preventing tissue proteolytic activity and reducing collagen degradation. Together with increased TGF-P 1 activity, PAI-1 activity and expression are increased in experimental models of aging and in aged individuals42, 43. PAI-1 is upregulated in aging-associated pathologies, including hypertension44. Increased PAI-1 is also recognised as a biomarker of cellular senescence in aging and hypertension45.
Connective tissue growth factor (CTGF)
Connective tissue growth factor is a 38KDa, cysteine-rich secreted, potent profibrotic factor implicated in fibroblast proliferation, cellular adhesion and ECM synthesis. CTGF expression in the vasculature is enhanced by several stimuli, including TGF-P 1, TNFa and mechanical stress 46. Ang
and vascular
II-induced vascular fibrosis is mediated by CTGF i
CTGF anti-sense oligonucleotides are protected against agonist-induced ECM protein expression ,
. CTGF may play an important role in arterial aging and vascular fibrosis as a number of experimental models have demonstrated increased levels of CTGF and associated vascular fibrosis
... . 48 49
with increasing age ' . Galectin-3
Galectin-3 (Gal-3) (LGALS3) is a 29-35 kDa carbohydrate-binding lectin expressed on the cell surface of many cell types including fibroblasts, endothelial and inflammatory cells. It is secreted mainly by activated macrophages and it is ligand-activated by oligosaccharides. Galectin-3 is also activated by other ligands including glycosylated matrix proteins, such as laminin, collagen, elastin, fibronectin and integrins. The cellular actions of galectin-3 lead to cell proliferation, adhesion and fibrosis. Galectin-3 has been shown to play an important role in fibrosis and tissue remodeling. In heart failure, plasma galectin-3 levels are increased50. In the recent PREVEND study (Prevention of REnal and Vascular END-stage disease) in which plasma galectin-3 levels were measured in 7968 individuals, plasma levels correlated positively with increasing age and cardiovascular risk factors, including hypertension51. Because of its role in fibrosis, galectin-3 is now considered by many as an important biomarkers of cardiovascular fibrosis. The precise mechanisms through which galectin-3
influences ECM remodeling and fibrosis are still unclear, although activation of JAK/STAT52 and
PKC pathways, oxidative stress and inflammation have been suggested. In addition, galectin-3 may directly increase production of ECM proteins. In rat vascular smooth muscle cells overexpression of galectin-3 enhanced aldosterone-induced collagen 1 synthesis, while
spironolactone or modified citrus pectin (galectin-3 inhibitor) reversed these effects54. Galectin-3 inhibition also attenuated cardiovascular fibrosis and left ventricular dysfunction in a mouse model of heart failure55.
The role of pro-hypertensive vasoactive factors in vascular aging and fibrosis
Many vasoactive factors activate pro-fibrotic pathways including Ang II, ET-1 and aldosterone (Figures 2,3). Downstream signaling involves activation of redox-sensitive genes and transcription factors, early growth response factor-1 and activation of TGF-P1, MMPs, galectin-3 and MAP kinases56-60. The aging vasculature is characterised by increased levels of Ang II5, angiotensin-converting enzyme (ACE)16, 30, 60, mineralocorticoid receptors61 and endothelin converting enzyme-1 (ECE-1)62, 63. As such, increased levels of these factors, their receptors and downstream targets could represent an important event during aging that lead to vascular stiffness.
Ang II signaling and vascular fibrosis
The renin-angiotensin-aldosterone system plays a central role in structural and mechanical changes in the vasculature. Ang II acts via activation of two receptors, AT1 and AT2, where AT1 plays a major role in the production of ECM proteins64-67. This is highlighted by studies demonstrating that antagonism of Ang II receptors results in decreased fibrosis68, 69. The precise signaling events involved in Ang II-induced vascular fibrosis are incompletely determined however, in mesangial cells TGF-P1 activity is increased by Ang II, an effect not observed when AP-1 binding sites or PKC and p38MAPK-dependent pathways are inhibited64. In addition, galectin-3 seems to be associated
with Ang II-induced fibrosis and its expression is related to severity of renal dysfunction in aging ; mice subjected to Ang II infusion develop cardiac fibrosis, an effect not observed in galectin-3 knock-out animals, furthermore, cultured fibroblasts exposed to galectin-3 have reduced collagen production and deposition59. Ang II-induced activation of p38MAPK is also associated with the
development and progression of fibrosis, commonly observed in aging and hypertension - . It has been suggested that Ang II induces activity of MMPs and TIMPs74-76 and upregulation of CTGF
during aging77-79.
Accumulating evidence implicates aldosterone as an important pathophysiological mediator in
cardiovascular remodeling by promoting vascular hypertrophy, fibrosis, inflammation and oxidative
stress80-82. Evidence from animal models and clinical trials of heart failure and hypertension demonstrate that chronic blockade of mineralocorticoid receptors, through which aldosterone signals,
reduces cardiovascular fibrosis. In rats, aldosterone infusion increases aortic media cross-sectional
83, 84
area associated with elevated collagen levels, particularly increased collagen I synthesis83, 84.
In the context of aging, aldosterone levels have been shown to decline in older age85, 86. This is associated with increased expression of mineralocorticoid receptors in intact vessels as well as in cultured vascular smooth muscle cells, and has been shown to correlate with markers of vascular fibrosis61. Whether increased signaling through mineralocorticoid receptors plays a role in vascular fibrosis associated with aging has yet to be confirmed.
ET-1 and vascular fibrosis
ET-1 is a secreted peptide, produced primarily in endothelial cells, following conversion of preproendothelin to proendothelin and subsequently to mature endothelin that has potent vasoconstrictor activity. The vascular actions of ET-1 are mediated by two distinct endothelin receptor subtypes: ETA and ETB receptors located on both vascular smooth muscle and endothelial cells. In addition to well-established hypertrophic and mitogenic properties, ET-1 can modulate ECM remodeling by stimulating fibroblast-induced collagen synthesis. ET-1 stimulates synthesis of
87, 88
collagen through both ETA and ETB receptor subtypes , . Reduced cardiac and renal MMP activity and expression have been reported following administration of ETA receptor antagonists89-91. Similarly, treatment with an endothelin antagonist normalizes expression of collagen I gene and
leads to the regression of renal vascular fibrosis and to improved survival .
Numerous findings have reported elevated ET-1 levels in healthy older adult humans93, 94 In cultured aortic endothelial cells, ET-1 synthesis is greater in cells obtained from older donors versus young
adult donors95. In Wistar-Kyoto (WKY) rats aging is associated with a 3.6-fold elevation in kidney ET-1 protein expression in the kidney. In rodent models, dual ETA/ETB receptor antagonism had no effect on the age-associated increase in aortic MMP-2 activity in WKY rats, but markedly reduced pro and active MMP-2 activity in aged hypertensive rats, demonstrating that ET-1 may represent an important mediator of vascular stiffness in aging in the presence of other vascular diseases62.
Conclusions
With ageing the vasculature undergoes structural and functional changes characterised by arterial remodelling, vascular fibrosis and stiffening, processes that are evident in aging and hypertension. Arterial stiffening is common occurring in over 60% in those older than 70 years and is a major independent predictor for serious cardiovascular events. Accordingly, there is a need to understand the fundamental processes that cause vascular stiffness so that mechanism-based therapeutic strategies can be developed to ameliorate or prevent processes of 'vascular aging' in hypertension and associated cardiovascular diseases. Arterial stiffening is caused primarily by excessive fibrosis due to excessive accumulation of vascular collagen and degradation of elastin. It is a dynamic phenomenon, which initially is an adaptive repair response that is reversible. However, the fibrogenic process is progressive leading to further worsening of arterial stiffness and fibrosis that gradually extends into the neighbouring interstitial space causing tissue and organ damage. A number of non-invasive methods are currently available to evaluate large artery stiffness in the clinical setting including carotid-femoral PWV. Increased PWV in aging and hypertension reflects increased arterial stiffness and is emerging as a biomarker for cardiovascular risk stratification. Perhaps over the next decade, PWV assessment may become a routine investigation in the clinical tool kit to better predict hypertension and cardiovascular disease.
Acknowledgements
Work from the author's laboratory was supported by grants from the British Heart Foundation (BHF)
(RG/13/7/30099). RMT is supported through a BHF Chair (CH/12/4/29762) and RAL is supported
by a PhD scholarship from FAPESP-Brazil (2012/12178-6).
There are no disclosures to declare
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Figure 1. The vascular phenotype in aging and hypertension.
With aging and during the development of hypertension, the endothelium, vascular wall and adventitia undergo functional and structural changes. Endothelial function is impaired and the vascular media is thickened. The adventitial extracellular matrix undergoes remodelling, with increased collagen deposition, reduced elastin content and increased pro-inflammatory cells. These processes contribute to vascular fibrosis and stiffening.
Figure 2. Vascular signalling mediating ECM remodelling, fibrosis and arterial stiffening in aging and hypertension.
Pro-hypertensive factors and physiological aging promote ECM remodelling through; activation of TGF-P and subsequently, MAPK and SMAD pathways, ROS production leading to MMP and CTGF activation and upregulation of Galectin-3. Subsequently, Collagen, fibronectin and proteoglycan deposition is increased leading to fibrosis and increased arterial stiffness. TGF, transforming growth factor; MAPK, mitogen activated protein kinase; ROS, reactive oxygen species; MMP, matrix metalloproteinase; PAI, plasminogen activator inhibitor; CTGF, connective tissue growth factor; TIMP, tissue inhibitory metalloproteinase; ECM, extracellular matrix; p, phosphorylation
Figure 3. Influence of pro-hypertensive factors and aging in the development of vascular fibrosis and arterial stiffening.
The renin-angiotensin-aldosterone system, acting through AT1R and MR, and ET-1 acting through ETR activate MMP's, CTGF and TGF-P signalling resulting in inflammation, oxidative stress and fibrosis leading to increased arterial stiffness. This process is also induced by ET-1 signalling through ETR, aldosterone signalling through MR and aging. ACE, angiotensin converting enzyme;
mineralocorticoid receptor; MMP, matrix metalloproteinase.
Intima
^Collagen Macrophages Calcification
Vascular Media
VSMC growth I^VSMC contraction n|/VSMC relaxation Inflammation Calcification sl/Elastin
Endothelium
sl/Endothelial relaxation ^Inflammation ^Permeability Pro-thrombotic
— Adventitia
ECM remodeling ^Collagen xUEIastin ^ Fibronectin Proteoglycans t TIMPs, M MPs Inflammation
Inactive TGF-ß —> Active TGF-ß
Pro-hypertensive Factors
Vascular smooth muscle cell
Aging —1
ECM Turnover
Angiotensin II
Angiotensinogen
Increased Collagen I Activation of MMPs Increased CTGF, TGF-JB signalling Decreased Elastin
Inflammation Oxidative stress Fibrosis
Blood vessel
Increased vascular stiffness
