(Hypertension. 1996;28:785-790.)
© 1996 American Heart Association, Inc.
Articles |
Vascular Hypertrophy and Remodeling in Secondary Hypertension
the Chair of Semeiotica and Metodologia Medica, Department of Medical Sciences (D.R., E.P., M.C., G.B., M.L.M., E.A.-R.), and Chair of Chirurgia Generale, Department of Surgical Sciences (P.M., S.M.G.), University of Brescia (Italy).
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Abstract |
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It has been proposed that several neurohumoral factors may be involved in the genesis of vascular structural changes (remodeling or hypertrophy) frequently observed in essential hypertension. Therefore, in this study we investigated vascular structural alterations of subcutaneous small resistance arteries in patients with secondary forms of hypertension. The study included 70 participants: 11 with pheochromocytoma, 13 with primary aldosteronism, and 17 with renovascular hypertension; 13 normotensive subjects and 16 patients with essential hypertension served as controls. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on a micromyograph, and media-lumen ratio, media thickness, remodeling index, and growth index were evaluated. Endothelial function was evaluated according to the dose-response curve to acetylcholine. In patients with either primary aldosteronism or renovascular hypertension, a marked increase in media-lumen ratio was observed, whereas in patients with pheochromocytoma, the extent of vascular structural alterations was similar to that observed in patients with essential hypertension. The increase in media-lumen ratio in patients with essential hypertension and with pheochromocytoma was mainly due to vascular remodeling (remodeling index, 93% to 94%), whereas in patients with renovascular hypertension, there was vascular growth (remodeling index, 70%; growth index, 53%). Patients with primary aldosteronism had an intermediate pattern compared with the other two forms of secondary hypertension. An evident impairment of endothelial function was observed in all four hypertensive groups. In conclusion, the renin-angiotensin-aldosterone system seems to be more powerful than the adrenergic system in inducing vascular growth.
Key Words: vascular resistance • hypertrophy • renin-angiotensin system • catecholamines • acetylcholine • endothelium-derived factor
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Introduction |
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The increased peripheral resistance that is the hallmark of hypertension in animals and humans can be largely ascribed to the consequences of alterations in the resistance arteries, consisting mainly of smaller arteries less than 400 µm and arterioles less than 100 µm in lumen diameter.1 2 3 The media-lumen ratio in small resistance arteries may be increased as a consequence of remodeling or cell growth.4 It has been proposed that several nonhemodynamic factors may be involved in the genesis of vascular structural alterations.5 6 The study of patients with secondary hypertension may help in the evaluation of the possible role of some neurohumoral factors in the development of vascular hypertrophy or remodeling.
An impairment of endothelial function, as evaluated by the vasodilator response to acetylcholine, has been detected in essential hypertension7 8 9 and may contribute to the imbalance between vasoconstriction and vasodilation. Also in secondary forms of hypertension, a reduced vasodilator response to acetylcholine in the forearm has been observed.10 Therefore, in this study, we investigated the structure and endothelial function of subcutaneous small resistance arteries in patients with secondary hypertension.
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Methods |
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Forty-one patients with secondary hypertension were included in the study: 11 with pheochromocytoma, 13 with primary aldosteronism, and 17 with renovascular hypertension. Data were compared with data obtained from 13 normotensive subjects and 16 patients with essential hypertension. The control hypertensive patients were considered to have borderline or established hypertension if their clinic blood pressure (average of three different sphygmomanometric measurements each performed on 3 separate days after a washout period of at least 2 weeks if the patient was previously treated with antihypertensive drugs) was greater than 140/90 mm Hg. The normotensive control subjects were considered normotensive if their systolic pressure was lower than 140 mm Hg and their diastolic pressure lower than 90 mm Hg. Clinic blood pressure was also evaluated, according to the previously mentioned criteria, in patients with secondary hypertension. All hypertensive patients had been previously treated for various periods of time with calcium channel blockers, angiotensin-converting enzyme inhibitors, diuretics, or ß-blockers.
Venous blood samples were taken with participants in the supine position, after a washout period of 2 weeks when appropriate, for measurement of plasma renin activity (radioimmunoassay, Renctk, Sorin Biomedica), plasma and urinary aldosterone (radioimmunoassay, Aldoctk, Sorin Biomedica), and plasma or urinary norepinephrine and epinephrine (high-performance liquid chromatography).11
All participants then underwent a biopsy of subcutaneous fat from the gluteal or anterior abdominal region. The biopsy of abdominal subcutaneous fat was taken during a surgical procedure—usually a cholecystectomy in normotensive and essential hypertensive individuals and adrenalectomy or a vascular surgical intervention on the renal arteries in patients with secondary hypertension—whereas in the remaining cases, a standard skin biopsy of the gluteal region (3 cm long, 0.5 cm wide, 1.5 cm deep) was performed.12 13 The percentage of skin biopsies taken from abdomen was similar in the five patient groups (about 20% to 25%). In a pilot study in three essential hypertensive patients submitted simultaneously to a biopsy of the subcutaneous fat from the gluteal or anterior abdominal region, no difference was observed in the morphology and function of the small resistance arteries (Table 1
).
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The protocol of the study was approved by the ethics committee of our institution (Medical School, University of Brescia), and informed consent was obtained from each participant. The procedures followed were in accordance with institutional guidelines.
Small arteries (average diameter about 140 to 250 µm in relaxed conditions, 2 mm long) were dissected from the subcutaneous fat of the biopsies and mounted as a ring preparation on an isometric myograph (410 A, JP Trading) by threading onto two stainless steel wires (40-µm diameter). The wires were attached to a force transducer and micrometer as previously described by Mulvany and coworkers.14 15 Vessels were warmed to 37°C and allowed to equilibrate for at least 30 minutes in physiological saline solution (PSS) with the following composition (mmol/L): NaCl 119, NaHCO3 24, KCl 4.7, KH2PO4 1.18, MgSO4 1.17, CaCl2 2.5, and glucose 5.5; the solution was kept constantly at 37°C and bubbled with 5% CO2 in oxygen. The vessel internal circumference was set to give a wall tension of 0.1 mN/mm.
Vessel wall and media thicknesses were measured at 12 sites, which were then averaged, with the use of a light microscope with immersion lens (Lab 20, Carl Zeiss SpA) at x600 magnification, which provides a resolution of 0.2 µm. Lower magnification was used for measurement of the distance between the wires and the length of the blood vessel. The resting tension–internal circumference relation was determined, and vessels were set to the normalized circumference L1, where L1=0.9 L100, and L100 is the internal circumference the vessels would have had in vivo when relaxed and under a transmural pressure of 100 mm Hg as described by Mulvany et al.14 15 From L1, the normalized internal diameter, l1, was calculated. Assuming that the cross-sectional area remains constant when the vessel is extended to L1, the wall and media thicknesses were automatically calculated in normalized conditions. Wall and media thicknesses as well as the media-lumen ratio of blood vessels in normalized conditions (vessels extended to L1) were obtained, assuming a constant wall and media volume, from wall and media cross-sectional areas calculated from wall and media thicknesses measured in unstretched vessels, as previously described.14 15 In our laboratory, the intra-assay coefficient of variation of the media cross-sectional area calculation is 10.4% (six vessels, 10 measurements in each vessel in a single session), and the interassay coefficient of variation is 11.2% (six vessels, 10 measurements in each vessel performed in two sessions by two different observers).
The remodeling index was calculated according to Heagerty and coworkers,4 expanding a previous observation of Baumbach and Heistad.16 It quantifies how much of the vascular structural alteration can be explained by a rearrangement of the same material around a narrowed lumen, without cell growth. The remodeled internal diameter can be calculated from the normalized external diameter of the hypertensive patients and from the cross-sectional area measured in the normotensive subjects. The remodeling index can be calculated from the remodeled internal diameter and from the normalized internal diameters observed in the normotensive subjects and hypertensive patients. The growth index can be calculated from the media cross-sectional area observed in the normotensive subjects and hypertensive patients.4 Because of the different method of calculation of remodeling index and growth index, the sum of the values is usually greater than 100%.
The vessels were then stimulated as follows: (1) three stimulations (2 minutes each) with PSS in which NaCl was substituted with KCl on an equimolar basis (KPSS), and two stimulations with KPSS containing 10 µmol/L norepinephrine; and (2) a cumulative dose-response curve to acetylcholine at the following concentrations: 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 µmol/L, 3 minutes per concentration, after precontraction with 5 µmol/L norepinephrine. The response to acetylcholine was expressed as the percent decrease of the wall tension obtained with norepinephrine precontraction.
If the vessels produced rhythmic activity, the response was measured from the mean active force for the last 20 seconds of each period. The responses of blood vessels are expressed as wall tension (active force divided by two times the segment length). Morphological and functional results from two different blood vessels in each subject were averaged to provide one mean observation per subject. For further details about the methods used, see References 17 through 19.
All data are expressed as mean±SD unless otherwise stated. One-way ANOVA and Bonferroni's correction for multiple comparisons were used for evaluation of differences among groups. Two-way ANOVA for repeated measures was used for dose-response curves to acetylcholine (groupxdose) (programs 7D, 1V, and 2V, BMDP Statistical Software Inc). Changes in media cross-sectional area are expressed also as 95% confidence intervals of the differences observed.
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Results |
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No differences in age, sex, height, weight, body surface area, or serum cholesterol and triglycerides were observed among the groups (Table 2
). The duration of hypertension (Table 2) and duration of previous antihypertensive treatment were similar in the four groups of hypertensive patients.
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Blood Pressure
In all groups of hypertensive patients, systolic and diastolic pressures during therapeutic washout were significantly increased compared with normotensive subjects, and no significant difference was observed among the hypertensive groups (Table 2
). Blood pressure values observed during antihypertensive therapy were similar in the four groups of hypertensive patients (essential hypertension, 147±14/91±10 mm Hg; pheochromocytoma, 144±19/90±7; primary aldosteronism, 146±21/91±8; renovascular hypertension, 150±23/94±13).
Humoral Data
A statistically significant increase in both plasma and urinary catecholamines was observed in patients with pheochromocytoma compared with the other groups (Table 2). In addition, plasma renin activity was increased in patients with renovascular hypertension and was reduced in patients with primary aldosteronism compared with the remaining groups (Table 2). Plasma and urinary aldosterone was significantly increased in patients with primary aldosteronism, whereas only plasma aldosterone was significantly increased in patients with renovascular hypertension.
Vascular Morphology
Media-lumen ratio was significantly increased in patients with essential hypertension and with pheochromocytoma compared with normotensive subjects. In patients with primary aldosteronism and with renovascular hypertension, an even more pronounced increase of media-lumen ratio was observed; in addition, the difference between patients with pheochromocytoma and with essential hypertension was statistically significant (Table 3). A similar pattern can be observed for media thickness, even if in this case no difference can be observed between patients with primary aldosteronism and those with pheochromocytoma or essential hypertension. The total wall thickness was significantly increased in patients with essential hypertension, primary aldosteronism, and renovascular hypertension compared with normotensive subjects. In patients with pheochromocytoma, the increase in total wall thickness compared with that in normotensive subjects was not statistically significant.
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Media cross-sectional area was significantly increased in patients with renovascular hypertension compared with normotensive subjects. Differences between patients with renovascular hypertension and with pheochromocytoma or essential hypertension were not statistically significant; however, the possibility of a type 2 error should be taken into account. Considering the relatively large variance of this parameter, we believed it helpful to calculate the 95% confidence intervals of the differences between groups. In the case of normotensive subjects versus patients with renovascular hypertension, the difference ranged from -1837 to -13 553 µm2 (average, -7695); in the case of normotensive subjects versus patients with primary aldosteronism, from -8196 to +2818 µm2 (average, -2689); in the case of patients with essential hypertension versus patients with renovascular hypertension, from -12 174 to -128 µm2 (average, -6151); and in the case of patients with pheochromocytoma versus patients with renovascular hypertension, from -12 079 to +217 µm2 (average, -6431).
In patients with essential hypertension and with pheochromocytoma, more than 93% of the increase in media-lumen ratio can be explained by a remodeling process (Table 3), whereas in patients with renovascular hypertension, the remodeling index was 70%, with a growth index greater than 50% (Table 3). In primary aldosteronism, the remodeling index was 90%, and therefore, the contribution of tissue growth to the genesis of vascular structural alterations was less pronounced than in renovascular hypertension. No difference in the morphology of vessels taken from the gluteal or anterior abdominal region was detected by one-way ANOVA. No statistically significant correlation between morphological data and age, plasma renin activity, aldosterone, or catecholamines was observed.
Endothelial Function
No significant difference among the different groups in the response to KPSS or in the precontraction with norepinephrine was observed (Table 4). The response to acetylcholine in patients with essential hypertension, pheochromocytoma, primary aldosteronism, and renovascular hypertension was significantly reduced (ANOVA, at least P<.05 in each case) compared with normotensive subjects (Table 4, Figure). No difference was observed among the different groups of patients with primary or secondary hypertension.
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Discussion |
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Sustained hypertension is usually associated with the presence of structural abnormalities in the resistance arteries,20 defined as precapillary arteries with a diameter less than 500 µm.1 2 3 21 It is still a matter of debate whether the structural changes of blood vessels precede hypertension and are thus involved in its pathogenesis to some degree or whether they result from the elevation of blood pressure.22 23 24 Until recently, few quantitative data existed concerning resistance artery structure. Over the past 10 years, such data have become available, particularly regarding the more proximal resistance vessels, the so-called small arteries. In both humans and animal models of genetic or experimental hypertension, an increase of media-lumen ratio of the small resistance arteries is a common feature.2 3 4 It has also been demonstrated in patients with essential hypertension that the increase in media-lumen ratio is mainly due to a remodeling process,11 25 26 27 that is to say, a rearrangement of otherwise normal material around a narrowed lumen, which was first observed in cerebral small arteries of spontaneously hypertensive rats.16 In small resistance arteries of genetically hypertensive rats (spontaneously hypertensive rats, transgenic rats), the remodeling index ranged from 72% to 96%, according to different studies (see Reference 4 for a review). Therefore, remodeling seems to play an important role in the altered structure of small arteries in essential hypertension.4 28
However, in animal models of secondary hypertension—such as aortic coarctation; one-kidney, one clip; two-kidney, one clip; deoxycorticosterone acetate–salt administration; and angiotensin II infusion—a more pronounced contribution of growth was observed,29 30 31 32 33 34 with remodeling indexes ranging from 7% to 89% and growth indexes ranging from 16% to 51%.29 30 31 32 33 In the present study, the morphological changes in small resistance arteries associated with secondary hypertension in humans were investigated. Two previous studies have demonstrated the presence of structural alterations in the carotid arteries in renovascular hypertension35 and primary aldosteronism36 in terms of an excess prevalence of plaques and an increased wall thickness, respectively. The present study has demonstrated that in patients with renovascular hypertension and, partially, also in those with primary aldosteronism, there is a more pronounced contribution of vascular growth to the genesis of vascular alterations as evaluated by changes in media-lumen ratio and media cross-sectional area. It is also well known that angiotensin II is involved in the processes that lead to cell growth,5 6 and aldosterone per se seems to possess a profibrotic effect.37 Angiotensin II also has been shown to induce vascular hypertrophy independently of its effects on blood pressure.33 38
In vitro studies have demonstrated that catecholamines have a trophic effect on smooth muscle cells.5 However, the prevalence of left ventricular hypertrophy in patients with catecholamine-producing tumors is not increased compared with essential hypertensive patients.39 40 41 Therefore, the in vivo growth-promoting effects of these hormones is questionable. On the other hand, an increased prevalence of cardiac structural alterations was observed in patients with primary aldosteronism and renovascular hypertension.41 Our data are in agreement with the previously mentioned observations in the human heart; in fact, we have observed a more pronounced degree of vascular alteration in those patients in whom the renin-angiotensin system was markedly activated, whereas in patients with an increased humoral adrenergic activity, the media-lumen ratio, albeit increased compared with normotensive subjects, was indistinguishable from that observed in patients with essential hypertension. Blood pressure, evaluated by clinic measurements, was not significantly different among the hypertensive groups. However, it is possible that clinic blood pressure may only partially reflect the 24-hour hemodynamic load; therefore, differences in vascular structure might partly be explained by differences in the severity of hypertension. On the other hand, in small subgroups of hypertensive patients (8 with essential hypertension, 4 with pheochromocytoma, 7 with primary aldosteronism, and 5 with renovascular hypertension), 24-hour noninvasive ambulatory blood pressure monitoring was performed, and no differences in 24-hour blood pressure or in daytime or nighttime blood pressure were observed, even if patients with secondary hypertension tended to have a slightly reduced nocturnal decline of blood pressure. Other possible confounding factors could be the duration of hypertension and duration and characteristics of antihypertensive treatment (type of drugs taken, blood pressure values during treatment); however, in our study, these factors were similar among the four hypertensive groups.
Although controversy rages with regard to the primacy of vascular structural alterations in essential hypertension, in secondary hypertension, there is little doubt that changes must follow a hormonal stimulus. Since angiotensin II, aldosterone, and catecholamines in addition to their growth-stimulating properties possess relevant hemodynamic effects, they may affect vascular structure both through their direct actions at the cellular level and (probably to a lesser extent) through the blood pressure rise. Subsequently, vascular structural changes may contribute to the maintenance of hypertension by amplifying any vasoconstricting stimulus.23
Patients with essential hypertension usually show the presence of endothelial dysfunction, as evaluated by the vasodilator response to acetylcholine.7 8 9 It is still unclear whether this is a primary abnormality or a consequence of the elevated blood pressure values. Data in animal models of genetic hypertension are in favor of a direct damage of the endothelial cells secondary to a prolonged increase of the hemodynamic load and of the shear stress.17 18 19 In hypertensive patients with primary aldosteronism or renovascular hypertension, an impairment of the vasodilator response to acetylcholine in the forearm was observed.10 Our data confirm these findings with a direct approach and extend the observations to patients with pheochromocytoma. It is well known that dyslipidemia could affect endothelial function; on the other hand, the lipid profile was within normal limits in all participants, and no differences in serum cholesterol or triglyceride levels were observed among the groups. Thus, our data support the hypothesis that in humans, endothelial dysfunction seems to be independent of the etiology of hypertension and of the degree of vascular structural alterations; on the contrary, it may be linked to the presence of hypertension per se.
In conclusion, marked vascular alterations were observed in patients with renovascular hypertension or, to a lesser extent, with primary aldosteronism. In patients with pheochromocytoma, the degree of vascular structural changes was similar to that observed in patients with essential hypertension. The increase in media-lumen ratio in patients with essential hypertension and with pheochromocytoma was mainly due to vascular remodeling (remodeling index greater than 94%), whereas in patients with renovascular hypertension, there was vascular growth of more than 50%. Patients with primary aldosteronism had an intermediate pattern compared with the other two forms of secondary hypertension. Therefore, the renin-angiotensin-aldosterone system seems to be more powerful than the adrenergic system in inducing vascular growth. An evident impairment of endothelial function, as evaluated with the dose-response curve to acetylcholine, was observed in all groups of hypertensive patients, regardless of the etiology of hypertension. Further studies with unbiased stereological methods are needed to properly address the problem of vascular changes at the cellular level (hypertrophy/hyperplasia).
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Acknowledgments |
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This work was a part of a project performed by the European Working Party on Resistance Artery Disease (EURAD), supported by the European Community under the BIOMED 1 programme. The authors thank Anthony Heagerty, MD, and Nicola Stephens, MD (Manchester, UK), for precious collaboration; Antonio Salvetti, MD, Fabrizio Arzilli, MD (Pisa, Italy), Achille C. Pessina, MD, Gianpaolo Rossi, MD (Padova, Italy), and Guido Garavelli, MD (Cremona, Italy), for providing some of the biological specimens; and Alessandra Panarotto for technical assistance.
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Footnotes |
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Reprint requests to Damiano Rizzoni, MD, UOP Scienze Mediche, University of Brescia, c/o 1a Medicina, Spedali Civili, 25100 Brescia, Italy. E-mail damiano.rizzoni@schering-pl.it.
Received April 1, 1996; first decision April 18, 1996; accepted May 27, 1996.
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 D. Rizzoni, S. Paiardi, L. Rodella, E. Porteri, C. De Ciuceis, R. Rezzani, G. E. M. Boari, F. Zani, M. Miclini, G. A. M. Tiberio, et al. Changes in Extracellular Matrix in Subcutaneous Small Resistance Arteries of Patients with Primary Aldosteronism J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2638 - 2642. [Abstract] [Full Text] [PDF]
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G. Bernini, F. Franzoni, F. Galetta, A. Moretti, C. Taurino, M. Bardini, G. Santoro, L. Ghiadoni, M. Bernini, and A. Salvetti Carotid Vascular Remodeling in Patients with Pheochromocytoma J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1754 - 1760. [Abstract] [Full Text] [PDF]
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 A. D. Smith, M. W. Brands, M.-H. Wang, and A. M. Dorrance Obesity-induced hypertension develops in young rats independently of the Renin-Angiotensin-aldosterone system. Experimental Biology and Medicine, March 1, 2006; 231(3): 282 - 287. [Abstract] [Full Text] [PDF]
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D. Rizzoni, E. Porteri, C. De Ciuceis, I. Sleiman, L. Rodella, R. Rezzani, S. Paiardi, R. Bianchi, G. Ruggeri, G. E.M. Boari, et al. Effect of Treatment With Candesartan or Enalapril on Subcutaneous Small Artery Structure in Hypertensive Patients With Noninsulin-Dependent Diabetes Mellitus Hypertension, April 1, 2005; 45(4): 659 - 665. [Abstract] [Full Text] [PDF]
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 G. Loirand, M. Rolli-Derkinderen, and P. Pacaud RhoA and resistance artery remodeling Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1051 - H1056. [Abstract] [Full Text] [PDF]
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E. L. Schiffrin and R. M. Touyz From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H435 - H446. [Full Text] [PDF]
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D. Rizzoni, E. Porteri, A. Giustina, C. De Ciuceis, I. Sleiman, G. E. M. Boari, M. Castellano, M. L. Muiesan, S. Bonadonna, A. Burattin, et al. Acromegalic Patients Show the Presence of Hypertrophic Remodeling of Subcutaneous Small Resistance Arteries Hypertension, March 1, 2004; 43(3): 561 - 565. [Abstract] [Full Text] [PDF]
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 D. Rizzoni, E. Porteri, G. E.M. Boari, C. De Ciuceis, I. Sleiman, M. L. Muiesan, M. Castellano, M. Miclini, and E. Agabiti-Rosei Prognostic Significance of Small-Artery Structure in Hypertension Circulation, November 4, 2003; 108(18): 2230 - 2235. [Abstract] [Full Text] [PDF]
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Q. Pu, M. F. Neves, A. Virdis, R. M. Touyz, and E. L. Schiffrin Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling Hypertension, July 1, 2003; 42(1): 49 - 55. [Abstract] [Full Text] [PDF]
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 W. F. Young Jr. Minireview: Primary Aldosteronism--Changing Concepts in Diagnosis and Treatment Endocrinology, June 1, 2003; 144(6): 2208 - 2213. [Abstract] [Full Text] [PDF]
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S. Kvist and M. J. Mulvany Contrasting Regression of Blood Pressure and Cardiovascular Structure in Declipped Renovascular Hypertensive Rats Hypertension, March 1, 2003; 41(3): 540 - 545. [Abstract] [Full Text] [PDF]
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A. Virdis, M. F. Neves, F. Amiri, E. Viel, R. M. Touyz, and E. L. Schiffrin Spironolactone Improves Angiotensin-Induced Vascular Changes and Oxidative Stress Hypertension, October 1, 2002; 40(4): 504 - 510. [Abstract] [Full Text] [PDF]
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F. M.A.C. Martens, B. Demeilliers, D. Girardot, C. Daigle, H. H. Dao, D. deBlois, and P. Moreau Vessel-Specific Stimulation of Protein Synthesis by Nitric Oxide Synthase Inhibition: Role of Extracellular Signal-Regulated Kinases 1/2 Hypertension, January 1, 2002; 39(1): 16 - 21. [Abstract] [Full Text] [PDF]
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S. Kvist and M. J Mulvany Reduced medication and normalization of vascular structure, but continued hypertension in renovascular patients after revascularization Cardiovasc Res, October 1, 2001; 52(1): 136 - 142. [Abstract] [Full Text] [PDF]
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H. D. Intengan and E. L. Schiffrin Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis Hypertension, September 1, 2001; 38(3): 581 - 587. [Abstract] [Full Text] [PDF]
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J. B. Park and E. L. Schiffrin ETA Receptor Antagonist Prevents Blood Pressure Elevation and Vascular Remodeling in Aldosterone-Infused Rats Hypertension, June 1, 2001; 37(6): 1444 - 1449. [Abstract] [Full Text] [PDF]
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D. Rizzoni, E. Porteri, D. Guelfi, M. L. Muiesan, U. Valentini, A. Cimino, A. Girelli, L. Rodella, R. Bianchi, I. Sleiman, et al. Structural Alterations in Subcutaneous Small Arteries of Normotensive and Hypertensive Patients With Non-Insulin-Dependent Diabetes Mellitus Circulation, March 6, 2001; 103(9): 1238 - 1244. [Abstract] [Full Text] [PDF]
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J. P. M. Wesselman, A. D. Dobrian, S. D. Schriver, and R. L. Prewitt Src Tyrosine Kinases and Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinases Mediate Pressure-Induced C-Fos Expression in Cannulated Rat Mesenteric Small Arteries Hypertension, March 1, 2001; 37(3): 955 - 960. [Abstract] [Full Text] [PDF]
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H. D. Intengan and E. L. Schiffrin Structure and Mechanical Properties of Resistance Arteries in Hypertension : Role of Adhesion Molecules and Extracellular Matrix Determinants Hypertension, September 1, 2000; 36(3): 312 - 318. [Abstract] [Full Text] [PDF]
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D. Rizzoni, E. Porteri, D. Guefi, A. Piccoli, M. Castellano, G. Pasini, M. L. Muiesan, M. J. Mulvany, and E. A. Rosei Cellular Hypertrophy in Subcutaneous Small Arteries of Patients With Renovascular Hypertension Hypertension, April 1, 2000; 35(4): 931 - 935. [Abstract] [Full Text] [PDF]
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M. J. Mulvany Vascular remodelling of resistance vessels: can we define this? Cardiovasc Res, January 1, 1999; 41(1): 9 - 13. [Full Text] [PDF]
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 D. Rizzoni, M. L. Muiesan, E. Porteri, M. Salvetti, M. Castellano, G. Bettoni, G. Tiberio, S. M. Giulini, C. Monteduro, G. Garavelli, et al. Relations between cardiac and vascular structure in patients with primary and secondary hypertension J. Am. Coll. Cardiol., October 1, 1998; 32(4): 985 - 992. [Abstract] [Full Text] [PDF]
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P. Moreau Endothelin in hypertension: A role for receptor antagonists? Cardiovasc Res, September 1, 1998; 39(3): 534 - 542. [Abstract] [Full Text] [PDF]
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D. Rizzoni, E. Porteri, M. Castellano, G. Bettoni, M. L. Muiesan, G. Tiberio, S. M. Giulini, G. Rossi, G. Bernini, and E. Agabiti-Rosei Endothelial Dysfunction in Hypertension Is Independent From the Etiology and From Vascular Structure Hypertension, January 1, 1998; 31(1): 335 - 341. [Abstract] [Full Text] [PDF]
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