Published online before print October 29, 2007, doi: 10.1161/HYPERTENSIONAHA.107.093260
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(Hypertension. 2007;50:1063.)
© 2007 American Heart Association, Inc.
Original Articles |
Hypertension and Hypercholesterolemia Differentially Affect the Function and Structure of Pig Carotid Artery
From the Divisions of Cardiovascular Diseases (D.V., M.G., D.M., O.G., L.O.L., A.L.) and Nephrology and Hypertension (E.D., L.O.L.), Mayo Clinic College of Medicine, Rochester, Minn; Departments of Clinical Pathology and Medicine and Excellence Research Center on Cardiovascular Diseases (C.N.), University of Naples, Naples, Italy; and Evans Department of Medicine and Whitaker Cardiovascular Institute (C.N.), Boston University, Mass.
Correspondence to Amir Lerman, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905. E-mail lerman.amir{at}mayo.edu
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Abstract |
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The purpose of this work was to compare the effects of hypertension and hypercholesterolemia on carotid endothelial function, structure, and vasa vasorum density. Seventeen pigs were randomized to a 12-week normal diet without (n=5), or with renovascular hypertension (HT; n=6), or to a high cholesterol diet (HC; n=6). Carotid arteries were studied by organ chambers (endothelial function) and microcomputed tomography (vasa vasorum), and tissue was processed for Sirius red staining and immunoblotting (vascular endothelium growth factor, endostatin, matrix metalloproteinase-9, and matrix metalloproteinase-2). HC and HT showed reduced vasodilation to acetylcholine as compared with controls, but HT also had a lower response to sodium nitroprusside. In addition, HT showed a higher content of organized collagen fibers and increased intima-media thickness. Vasa vasorum density was increased in HC but not in HT. Both HT and HC showed a proangiogenetic biochemical milieu (higher vascular endothelium growth factor, matrix metalloproteinases, and lower endostatin), but this was more pronounced in HC. Both hypertension and hypercholesterolemia induce endothelial dysfunction in the carotid artery. However, hypertension is also associated with greater fibrosis and vascular wall thickening, which might impair endothelium-independent vasorelaxation and vasa vasorum growth. Hypercholesterolemia is, in turn, associated with vasa vasorum neovascularization. These data suggest that carotid atherosclerosis can evolve through different mechanisms in relation to different risk factors.
Key Words: carotid artery • atherosclerosis • hypertension • hypercholesterolemia • vasa vasorum • endothelium
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Introduction |
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Stroke is a leading cause of death in Western countries, and in the majority of the cases it is the consequence of an acute complication of an atherosclerotic carotid plaque. Risk factors for carotid atherosclerosis include the traditional cardiovascular risk factors, and, in particular, hypertension plays a major role.1 Although in the past hypercholesterolemia was not considered a determinant contributor to cerebrovascular disease,2,3 recent epidemiological studies and clinical trials with lipid-lowering drugs demonstrated a clear relation between serum cholesterol levels and carotid atherosclerosis, as well as with the risk of stroke.1
Both hypertension and hypercholesterolemia are characterized by similar proatherogenic hallmarks, including endothelial dysfunction, vascular inflammation, and oxidative stress. However, the consequences of the action of these 2 risk factors on the arterial wall might be substantially different. Indeed, different cardiovascular risk factors influence atherosclerosis development favoring preferential plaque characteristics, eventually leading to the formation of morphologically different lesions.4,5 Experimental analysis of the interaction between hypertension and hypercholesterolemia on the mechanisms of early atherosclerosis indicates that hypertension, per se, induces adaptive remodeling, whereas for the maladaptive (atherogenic) intima-media thickening, hypercholesterolemia might be necessary.6
The vessel wall thickening leads to a progressive ischemia within the arterial wall that can, in turn, contribute to the activation of proatherosclerotic mechanisms and, consequently, to plaque formation and progression. Furthermore, the relative ischemia of the arterial wall can activate compensatory neovascularization within the vasa vasorum (VV) system to normalize oxygen supply, mainly through the stimulation of hypoxia inducible factor (HIF)-1
, which, in turn, increases vascular endothelial growth factor (VEGF).7 This proangiogenetic pathway can also be enhanced by the increase of vascular oxidative stress, which upregulates HIF-1,8 and by vascular inflammation associated with hypertension and hypercholesterolemia. Antiangiogenetic factors, such as endostatin,9 and matrix remodeling enzymes, such as matrix metalloproteinases (MMPs),10 are also important systems in the regulation of the angiogenetic process.
Despite being a compensatory mechanism, VV neoangiogenesis might eventually contribute to plaque progression and, in the late phases of atherosclerosis, to its destabilization by facilitating the recruitment of circulating precursors of inflammatory cells, intraplaque hemorrhage, and thrombosis.11 We have demonstrated previously that the VV neovascularization can even precede the development of endothelial dysfunction,12 which is generally considered the earliest stage of atherosclerosis.
In humans it is difficult to differentially study the effect of hypertension and hypercholesterolemia on the early phases of atherosclerosis development, because they are frequently associated in clinical practice,13 cluster with other risk factors, and are recognized in later phases.14 Therefore, we designed the present study to test the hypothesis that in the early phases of carotid atherosclerosis, hypertension, and hypercholesterolemia might differentially affect arterial function and structure. In particular, we evaluated the effect of these risk factors on endothelial function, local and systemic oxidative stress, carotid structure, angiogenetic pathway, and VV neovascularization in porcine experimental models of hypertension and hypercholesterolemia.
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Materials and Methods |
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Seventeen female cross-bred domestic pigs, 3 months of age, were randomized to be fed a normal diet ad libitum for 12 months, without or with hypertension induced by placement of a local irritant stent in the left renal artery (groups N, n=5, and HT, n=6, respectively) as described previously,15 or a high-cholesterol diet (group HC; n=6). At the end of the study, blood samples were collected for assessment of plasma lipid and oxidative stress parameters. Animals were then euthanized, and the vascular block, including the aortic arch and subclavian and carotid arteries, was immediately harvested and placed into a cold modified Krebs-Ringer bicarbonate solution. After removal of vascular specimens, 1 internal carotid artery was processed for tissue analysis and endothelial function assessment; the rest of the block was processed for microcomputed tomography analysis of VV architecture. All of the procedures respected the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Mayo Foundation Institutional Animal Care and Use Committee. For details, please see the data supplement available at http://hyper.ahajournals.org.
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Results |
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After a 12-week follow-up, the 3 groups showed similar body weight (N: 57.8±1.5 kg; HC: 59.4±2.4 kg; HT: 56.0±3.5 kg). HT had higher systolic, diastolic, and mean arterial pressure values (140±4/104±4/124±4 mm Hg) as compared with N (125±3/91±3/114±3 mm Hg; P<0.01) and HC (124±3/90±2/113±3 mm Hg; P<0.01). Compared with N and HT, HC had significantly (P<0.001) higher serum levels of total (N: 1.89±0.13; HC: 9.81±0.85; HT: 1.92±0.15 mmol/L), high-density lipoprotein (N: 0.83±0.08; HC: 2.54±0.21; HT: 0.78±0.10 mmol/L) and low-density lipoprotein (LDL) cholesterol (N: 0.91±0.13; HC: 7.05±0.75; HT: 1.01±0.10 mmol/L).
Carotid Endothelial Function
Maximal vasorelaxation to acetylcholine was significantly lower in HT (18.4±5.7%) and HC (13.7±4.5%) as compared with N (48.1±6.1%; P<0.001 for both), and no difference was observed between HC and HT (Figure S1A). Calcium ionophore induced a similar vasorelaxation in N (42.0±0.8%) and HC (43.8±1.0%), but did not affect HT (3.1±0.91%; P<0.001 versus N; Figure S1B). Moreover, HT were characterized by a significantly reduced response to sodium nitroprusside (maximal relaxation 61.6±7.9%) as compared with N (85.1±3.4%; P<0.05), whereas the response to sodium nitroprusside in HC was similar to the response in N (82.6%±1.8; Figure S1C).
Systemic and Local Oxidative Stress
HC showed significantly higher levels of LDL malondialdehyde and LDL relative electrophoretic mobility and lower LDL lag time as compared with N and HT (Table). Plasma thiobarbituric acid reactive substance levels in both HC and HT were higher than in N (Table).
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Dihydroethidium (DHE) staining of carotid arteries demonstrated an increased production of superoxide anion in specimens from HT and HC, particularly in the endothelial layer (percentage of intima DHE positive nuclei: N: 33.6±7.1%; HC: 77.2±7.9; HT: 71.4±7.4; P<0.01 for both HC and HT versus N; Figure 1).
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Histology and Collagen Content
Elastic van Gieson staining demonstrated a significant increase in intima-media thickness in carotid arteries from HT (0.77±0.06 mm) as compared with N (0.54±0.04 mm; P<0.05) and HC (0.59±0.02 mm; P<0.01; Figure 2). The groups had similar lumen diameters (N: 0.73±0.09 mm; HC: 0.90±0.10 mm; HT: 0.82±0.05 mm; Figure 2). Sirius red staining (Figure 2) did not show any difference among the groups in the content of thinner collagen fibers in the media, whereas a nonsignificant tendency to an increase in thicker fibers was observed in HT. On the contrary, the adventitia of HT was characterized by a significantly decreased content of thinner collagen fibers and an increased content of thicker and organized fibers (Figure 2).
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Carotid VV
Microtomographic morphometric parameters of carotid arteries from the 3 groups of pigs are shown in Table. Despite similar lumen areas, HT showed higher vessel wall areas as compared with N and HC. Moreover, whereas no difference was present between N and HT, HC were characterized by a significantly increased VV count, area, and spatial density (Table and Figure S2). No difference was observed in the average diameter of VV.
Angiogenesis Pathway
Immunoblotting analysis for VEGF demonstrated a significant increase in HC and a tendency to increase in HT as compared with N (Figure 3). Immunostaining confirmed the higher expression of VEGF and also demonstrated increased expression of HIF-1 in the outer media in both HC and HT (percentage of positive media nuclei: N: 10.7±1.5%; HC: 30.7±6.3%; HT: 45.9±7.8%; P<0.05 for HC and HT versus N; Figure 3). Moreover, immunoblotting showed lower expression of antiangiogenetic endostatin in both HC and HT than in N (Figure 3). Finally, HC carotid arteries showed increased expression of MMP-9 and a borderline increase in MMP-2 as compared with N carotid arteries, whereas in arteries from HT, both metalloproteases were nonsignificantly increased (Figure 3).
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P<0.05 vs HC; 
P<0.05 vs N; 
P=0.05 vs N.We found an inverse borderline significant correlation between red-orange staining with Sirius red and VV density (r=–0.57; P=0.08). Correlations between other studied parameters were not statistically significant.
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Discussion |
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The present study demonstrates a differential effect of hypercholesterolemia and hypertension on porcine carotid artery function and structure in the early phases of atherosclerosis. In particular, both cardiovascular risk factors induce an increase in systemic and vascular oxidative stress, associated as expected with reduced vasorelaxation to endothelium-dependent stimuli. However, hypertension is also associated with a decrease in the response to endothelium-independent stimulus, increased vascular fibrosis, and media thickening as compared with N and HC. Moreover, only HC showed a significant increase in carotid artery VV density. These data suggest that, in the carotid artery, hypertension has a greater effect in inducing the early atherosclerotic structural hypertrophic modification as compared with hypercholesterolemia. This latter, on the other hand, induces VV neovascularization, which is potentially a crucial factor for the progression of the disease. The current study suggests that hypercholesterolemia and hypertension may favor the development of different functional and structural changes in the early phases of carotid atherosclerosis.
Carotid Vascular Relaxation
Hypertension and hypercholesterolemia are well known to induce functional and structural alteration in the vessel wall, predisposing to atherosclerosis. Both risk factors are associated with increased systemic and vascular oxidative stress, leading to a reduced NO bioavailability and endothelial dysfunction.16 In the present study we confirm the presence of similarly reduced vasorelaxation to acetylcholine in HC and HT, associated with increased superoxide production in the endothelial layer and increased systemic oxidative stress. On the contrary, the response to calcium-ionophore was found impaired in HT, and was normal in HC, consistent with previous results in hypercholesterolemic animals and humans.17,18 Moreover, diversely from previous data in the pig coronary circulation,19,20 in HT a significant decreased response to sodium nitroprusside was also detected, and this is consistent with that observed in the carotid district of rodent models of hypertension.21,22 Although we cannot rule out the possibility of a reduced responsiveness of HT smooth muscle cells to the relaxant, the presence of structural modifications within the carotid arterial wall of HT seems to be the most probable mechanism, by restraining smooth muscle cells relaxation,23 because the vasorelaxation to sodium nitroprusside is reversed by antifibrotic treatment.22 Conceivably, in our model, the observed increased intima-media thickness and the adventitial fibrosis contribute to the arterial stiffening and to the consequent impaired vasorelaxation. In particular, in the Sirius red staining, HT showed an increased signal in the spectrum of the orange-red wavelength, indicating accumulation of thick and more organized collagen fibers.24
Carotid VV
The presence of hypercholesterolemia has been demonstrated to stimulate VV neoangiogenesis in several animal models,25,26 and we demonstrated previously by microcomputed tomography the presence of VV within the carotid artery in normal pigs.27 The present study confirms the effect of hypercholesterolemia in inducing VV neovascularization in the carotid district, conceivably through an activation of the HIF-1-VEGF axis. This phenomenon in the early stages is potentially protective, protecting the vascular wall from the effects of a relative hypoxia, such as the increase in vascular oxidative stress, inflammation, and fibrosclerosis. In our study, the lack of arterial wall thickening in HC suggests that the main drive to vessel wall neovascularization might not be represented by local hypoxia but could rather be related to the increased oxidative stress, which is capable of activating HIF-1.28
In the long term, the consequent increased exchange surface between the arterial wall and the circulating blood might conceivably favor the infiltration of lipids, oxidized lipids, inflammatory cells, and mediators, key mechanisms of atherosclerotic plaque formation.29 On the other hand, HT were characterized only by a smaller and nonsignificant increase in VV count as compared with N, in line with previous results in canine30 and porcine31 renovascular hypertension models. This, together with the significant increase in intima-media thickness, resulted in a VV density that was not different from N. Although in a previous work32 hypertensive rats were characterized by a significant increase in the number of aortic VV as compared with control animals, a parallel increase in vessel wall area was observed, conceivably determining nonchange in VV density. Partly in accordance with Kuwahara et al,32 we found an increased expression of HIF-1 and, to a lesser extent, of VEGF in carotid arteries from HT. We also observed an actual increase in VV count, that, however, was not significant. The present results suggest that, although in hypertension there is a drive toward neoangiogenesis, as supported by the increased expression of HIF-1, VEGF, MMPs, and the decreased expression of endostatin, the collagen accumulation and organization might limit the sprouting of new vessels. Moreover, although HT and HC showed a similar increase in the expression of HIF-1, this was followed by a greater increase in VEGF in HC. Because HIF-1 is a major determinant for the proliferation of smooth muscle cells,33 it is possible that, in the presence of hypertension, characterized by increased wall stress, the HIF-1 downstream mediators tend to preferentially foster smooth muscle cell proliferation and vascular fibrosis to restore normal wall stress. On the contrary, the more favorable hemodynamics of HC allows the HIF-1-VEGF pathway to promote neovessel sprouting.
The current study is consistent with what we found previously in the coronary circulation,25 showing a stronger drive toward vascular collagen accumulation in hypertension than in hypercholesterolemia. However, different from the coronary district,31 the hypertension-related carotid artery fibrosis results in an early impairment on the vascular wall distensibility and response to endothelium-independent stimuli. We can speculate that the elastic nature of the carotid artery tends to make it more prone to change its matrix structure by accumulating collagen. However, the clear mechanisms for the different responses of distinct vascular districts to cardiovascular risk factors are not known.
Implications for Atherosclerosis
It was demonstrated previously that the morphology of atherosclerotic plaques, which is a key determinant for the development of complications and clinical events, is differentially influenced by different cardiovascular risk factors4,5; in particular, hypertension is more often associated with a granulomatous whereas hypercholesterolemia is associated with a xanthomatous plaque phenotype.4
According to the response-to-injury theory of atherosclerosis, mechanical or chemical factors induce damage to the endothelium, followed by proliferation of smooth muscle cells, infiltration of leukocytes, and accumulation of (oxidized) lipids.34 Chobanian35 showed that hypertension might represent one of the initiators of atherosclerosis, but it might not be able to induce the formation of atherosclerotic plaque without the presence of hypercholesterolemia. Indeed, although both cardiovascular risk factors are clinically associated with carotid intima-media thickening, hypertension, per se, is able to induce adaptive remodeling, but for the maladaptive (atherogenic) intima-media thickening, hypercholesterolemia might be necessary.6
Hypertension and hypercholesterolemia may share similar proatherosclerotic mechanisms, such as vascular oxidative stress, endothelial dysfunction, and vascular inflammation; however, from the early phases, they seem to favor different functional and structural modifications in the vascular system. Mechanical stress, the related gene expression in hypertension, and the overload of native and oxidized forms of endogenous lipids in hypercholesterolemia are possible implicated differential mechanisms.
Although hypertension is the main risk factor for stroke, we can speculate that it is crucial for the initiation of the process by inducing endothelial dysfunction/damage35 and for the complication of the mature plaque by means of mechanical trauma. Hypercholesterolemia, in turn, through the related increased neovascularization of the arterial wall, might be fundamental for the further growth and development of the mature plaque; accordingly, hypercholesterolemia, but not hypertension, is associated with an unstable plaque phenotype.36
A limitation of the present study is represented by the lack of a group of animals with both hypertension and hypercholesterolemia. Further studies analyzing the interaction of the 2 risk factors might be useful to understand the dynamics of carotid atherosclerosis and its later consequences. Moreover, the relatively small number of animals did not allow us to find significant correlations among the studied parameters. Finally, the observed effects relate to the experimental animal models used in the present study, and it is not clear whether they can be applied to other forms of hypertension and hypercholesterolemia. In particular, we used a model of renovascular hypertension in which the activation of the renin-angiotensin system might foster vascular fibrosis. It is possible that in other models of hypertension, such as aortic coarctation or in spontaneously hypertensive rats, these phenomena might be different for some aspects. Similar considerations are also valid for diet-induced hypercholesterolemia with respect to apolipoprotein E–deficient mice. However, although further studies are needed to confirm the present data, the porcine model reasonably resembles human vascular physiology and pathophysiology, and the experimental models that we used can be considered reliable surrogates of the early atherosclerotic process.37
Perspectives
The present study confirms that hypertension and hypercholesterolemia represent noxious factors for the carotid circulation by promoting various mechanisms of the atherosclerotic process. However, the 2 risk factors are characterized by the development of partially different features of atherosclerosis with potentially different roles in the onset, progression, and complication of the disease. Future research should be directed to elucidate these aspects, which may have important clinical implications for the prevention and treatment of atherosclerosis.
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Acknowledgments |
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Sources of Funding
This work was supported by the National Institutes of Health (HL63282 and HL-03621), the Italian Society of Hypertension, the University of Pisa, the Italian Ministry of University (PRIN 2002), and the Mayo Foundation.
Disclosures
None.
Received May 9, 2007; first decision May 17, 2007; accepted September 26, 2007.
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