This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rizzoni, D. Articles by Rosei, E. A. Search for Related Content PubMed PubMed Citation Articles by Rizzoni, D. Articles by Rosei, E. A. Related Collections Hypertension - basic studies Smooth muscle proliferation and differentiation Mechanism of atherosclerosis/growth factors

(Hypertension. 2000;35:931.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Cellular Hypertrophy in Subcutaneous Small Arteries of Patients With Renovascular Hypertension

Damiano Rizzoni; Enzo Porteri; Daniele Guefi; Alfonso Piccoli; Maurizo Castellano; Giancarlo Pasini; Maria Lorenza Muiesan; Michael John Mulvany; Enrico Agabiti Rosei

From the Chair of Internal Medicine, Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy, and the Department of Pharmacology (M.J.M.), University of Aarhus, Aarhus, Denmark.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract—Structural alterations of small arteries in patients with essential hypertension are characterized by inward eutrophic remodeling. However, small arteries in patients with secondary hypertension, as well as in experimental models of hypertension with high circulating renin, are characterized by inward hypertrophic remodeling, which is characterized by smooth muscle cell hypertrophy in animal models. The aim of our study was to determine whether remodeling of subcutaneous small arteries in patients with secondary forms of hypertension is associated with smooth muscle cell hypertrophy and/or alterations in the elastic modulus of the vessel wall. Fifteen patients with renovascular hypertension, 9 with primary aldosteronism, and 13 with essential hypertension and 9 normotensive subjects were included in the study. A biopsy of subcutaneous fat was taken from all subjects. Small arteries were dissected, and morphology was determined on a micromyograph. Unbiased estimates of cell volume and number were made in fixed material. From the resting tension–internal circumference relation of the small arteries, the incremental elastic modulus was calculated and plotted as a function of wall stress. Blood pressure was greater in patients with essential hypertension, renovascular hypertension, or primary aldosteronism than in normotensive subjects, but no significant difference was observed among the 3 groups of hypertensive patients. The media/lumen ratio, the medial cross-sectional area, and the smooth muscle cell volume were significantly greater in patients with renovascular hypertension than in normotensive subjects and patients with essential hypertension. No difference in cell number or in the elastic properties was observed among the 4 groups of subjects. In conclusion, our data demonstrate for the first time that a pronounced activation of the renin-angiotensin-aldosterone system is associated with vascular smooth muscle cell hypertrophy in human hypertension in a manner similar to that found in animal models.

Key Words: hypertension, secondary • hypertrophy • remodeling • renin-angiotensin-aldosterone system • vascular resistance

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
It is well established that structural changes of small arteries are associated with hypertension.^{1 2 3} These alterations include a decreased luminal diameter and an increased medial thickness,^{3 4 5 6} thus leading to an increased media/lumen ratio. The media/lumen ratio in small arteries may be increased as a consequence of eutrophic remodeling (ie, a rearrangement of otherwise normal material around a narrowed lumen) or of hypertrophic remodeling (hypertrophy or hyperplasia of vascular smooth muscle cells).^{7 8} Present evidence indicates that in animal models of genetic hypertension and in patients with essential hypertension, vascular structural abnormalities of small arteries are, in general, characterized by an inward eutrophic remodeling,^{7 8} as evaluated by the calculation of remodeling and growth indices.^{7 9} Similar conclusions have been drawn when structural abnormalities were investigated by use of an unbiased stereological technique, the so-called disector technique,¹⁰ to evaluate at the cellular level the structural characteristics of small arteries. No difference in the vascular smooth muscle cell volume or number per unit of vessel length was observed between normotensive subjects and patients with essential hypertension.¹¹ Normal cell size was also found in mesenteric small arteries of spontaneously hypertensive rats.¹²

In contrast to genetic hypertension, in experimental animal models of hypertension with high circulating renin or angiotensin II (eg, 2-kidney, 1-clip rats and rats with chronic angiotensin II infusion), hypertrophic remodeling of small resistance vessels was observed.⁷ This was also the case for 1-kidney, 1-clip rats, in which an increase of vascular smooth muscle cell volume was observed, confirming the presence of hypertrophic remodeling.¹³ In hypertensive patients with activation of the renin-angiotensin-aldosterone system (ie, in renovascular hypertension), we have previously shown the presence of inward hypertrophic remodeling of subcutaneous small arteries.¹⁴ However, that study did not show the cellular basis for this alteration (increased smooth muscle cell number or volume), nor did it determine whether the apparent remodeling observed might be due to altered elastic properties of the vascular wall.^{7 15} To obtain information about the cellular structure and vessel elastic properties, we decided to start a study that would investigate a population of patients with renovascular hypertension, primary aldosteronism, or essential hypertension and compare those patients with normotensive controls. We have determined (1) the cellular basis for the structural characteristics of subcutaneous small arteries by use of the disector technique¹⁰ and (2) the elastic properties of the resistance arteries.¹⁶ Some of the subjects studied (<40%) were those investigated in 1996.¹⁴

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patients and Procedures
Forty-six subjects were included in the study: 15 patients with renovascular hypertension, 9 with primary aldosteronism, and 13 with essential hypertension. Data were compared with those obtained in 9 normotensive subjects. Hypertensive patients had a clinical blood pressure measurement (average of 3 different sphygmomanometric measurements, each performed on 3 separate days, after a washout period of at least 2 weeks if previously treated with antihypertensive drugs) >140/90 mm Hg. Normotensive control subjects had a systolic blood pressure <140 mm Hg and a diastolic blood pressure <90 mm Hg. All hypertensive patients had been previously treated for various periods of time with calcium channel blockers, angiotensin-converting enzyme inhibitors, diuretics, or ß-blockers. There was no statistically significant difference in the therapeutic regimens of the different groups. 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. Details about the micromyographic technique of evaluation of small resistance artery morphology (ring preparation on steel wires)^{14 17 18 19 20 21} and about the radioimmunoassay measurement of levels of plasma renin activity and plasma/urinary aldosterone were previously reported.¹⁴

When the micromyograph measurements were complete, the bathing solution was changed to calcium-free saline for 10 minutes to prevent a vasoconstrictive effect of the fixative. With the arteries still on the wires, the solution was changed to fixative (2% buffered glutaraldehyde). The vessels were removed from the wires, washed in physiological saline solution, preembedded in agar to maintain orientation, and finally embedded in Historesin (Technovit 7100, Heraeus Kulzer). In each artery from a point approximately halfway between where the mounting wires had been, a series of three to five 3-µm serial sections parallel to the vessel axis were made on a precision microtome (Historange, LKB). All sections were placed on glass slides, coded, and stained with Giemsa stain.

Unbiased estimates of smooth muscle cell number within the arteries were determined by use of the disector principle,¹⁰ as described previously.¹³ In brief, 2 successive sections were placed under 2 specially equipped microscopes projecting the images of the sections side by side onto a tabletop at a total magnification of x1650. The number of nuclei present in the first, but not in the second, section and the number in the second, but not in the first, section were counted. Ten areas in each vessel were marked and counted. From cell numerical density and volume fraction of media containing smooth muscle cells (determined by point counting), the mean cell volume was calculated. Additionally, the following parameters were calculated: average nucleus length, cell length, cell cross-sectional area, number of cell layers, and number of cells per unit vessel length. The equations used for the calculation of the previously mentioned morphological parameters have been reported previously (eg, References 12 and 21^{12 21} ).

The incremental elastic modulus was calculated from the resting tension–internal circumference relation (T-L relation) determined at the start of the experiment in connection with the normalization process, together with the morphological measurements, as described previously.¹⁶ From the T-L relation, exponential curves were fitted, and the internal circumference (L) for each vessel at wall tension (T) levels of 0.25, 0.5, 1, 1.5, 2, 2.5, and 3 N/m were determined by interpolation. The wall thickness (w) at this T level was calculated from the morphological measurements on the basis that the wall cross-sectional area, wx(L+xw), is constant. The incremental elastic modulus was defined as (dT/dL)x(L/w), where dT/dL is the slope of the T-L relation at internal circumference L. The modulus has been related to the wall stress, =T/w.

The intrapatient coefficient of variation for calculation of the incremental elastic modulus ranged between 33% and 16% (depending on the level of stretch), whereas that for calculation of wall stress ranged between 13% and 14%.

Statistical Analysis
In all cases, the parameter values for each subject were taken as the average values obtained from the 2 vessels in each experiment. Data are expressed as mean±SEM, unless otherwise stated. One-way ANOVA and the Bonferroni correction for multiple comparisons were used to evaluate differences among groups. A nonparametric approach (Mann-Whitney rank sum test) was adopted for those variables that were not normally distributed.

The mechanical properties of the vessels were evaluated by linear regression (elastic modulus versus stress). A separate analysis of groups by use of tests of equality of lines (difference in slopes and/or intercepts) across groups was performed. Differences in the previous treatments were compared by a ² test. Each class of drugs was considered separately (eg, calcium antagonist versus no calcium antagonists) (BMDP Statistical Software programs 7D, 3S, 1R, 4F, and 1V, BMDP Statistical Software Inc).

	Results

Top Abstract Introduction Methods Results Discussion References

 
Demographic and Clinical Data
The 4 groups of subjects did not differ by age, gender, height, weight, serum cholesterol or triglyceride levels, or smoking habits. As expected, systolic and diastolic blood pressure during therapeutic washout was greater in the 3 groups of hypertensive patients (patients with essential hypertension, 162/99±2.22/4.94 mm Hg; patients with primary aldosteronism, 170/103±4.33/3.00 mm Hg; and patients with renovascular hypertension, 163/104±4.13/3.10 mm Hg) than in normotensive subjects (127/79±2.67/2.33 mm Hg, P<0.001 versus any hypertensive group). The data obtained were similar to those reported in a previous publication.¹⁴ Blood pressure values recorded during antihypertensive treatment were as follows: patients with essential hypertension, 143/92±4.11/2.62 mm Hg; patients with primary aldosteronism, 143/90±4.09/2.88 mm Hg; and patients with renovascular hypertension, 145/95±4.24/3.01 mm Hg. Approximately 60% of all patients were on a monotherapy; 40% were on a combination therapy.

The known duration of hypertension was 3 to 4 years in all hypertensive patients, and no significant difference was observed in the previous antihypertensive treatment (Table 1).

View this table: [in this window] [in a new window]   Table 1. Previous Antihypertensive Therapy in Hypertensive Patients

Hormones
Plasma renin activity and plasma or urinary aldosterone levels were similar to those previously reported.¹⁴

Vascular Morphology
Similarly, the morphological data were similar to the data previously reported.¹⁴

Cellular Morphology
No difference in the number of cells per segment length, cell length, and cell layers was observed among all groups of normotensive subjects and hypertensive patients (Table 2). The smooth muscle cell volume was significantly greater in the resistance arteries of patients with renovascular hypertension than in patients with essential hypertension and in normotensive subjects (Table 2). The cell volume in patients with primary aldosteronism did not differ significantly from that observed in any of the other groups.

View this table: [in this window] [in a new window]   Table 2. Morphological Characteristics of Subcutaneous Small Resistance Vessels at the Cellular Level

Elastic Properties
To characterize the passive elastic features of the vessel, the incremental elastic modulus was calculated and plotted as a function of wall stress. It is apparent that there was no significant difference among the 4 groups of subjects (Figure).

View larger version (22K): [in this window] [in a new window]   Figure 1. Incremental elastic modulus plotted as a function of the wall stress of isolated subcutaneous resistance arteries from 15 patients with renovascular hypertension (RVH), 9 with primary aldosteronism (PA), 13 with essential hypertension (EH), and 9 normotensive subjects (NT). The vertical and horizontal bars indicate the SEM. No significant difference among the groups was observed by use of a test of equality of lines (difference in slopes and/or intercepts) or by comparing the maximum values with 1-way ANOVA.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study demonstrated for the first time that (1) an increased medial cross-sectional area in the subcutaneous resistance arteries of patients with renovascular hypertension is associated with smooth muscle cell hypertrophy, and (2) structural alterations in small resistance arteries of patients with essential or secondary hypertension are not associated with changes in the mechanical properties.

The observation of smooth muscle cell hypertrophy in small resistance arteries of patients with renovascular hypertension is in contrast to previous findings in resistance arteries from patients with essential hypertension, in which the eutrophic remodeling is not associated with altered smooth muscle cell number or volume. The study confirms previous animal studies and indicates that a pronounced activation of the renin-angiotensin-aldosterone system is associated with vascular smooth muscle cell hypertrophy in humans also.

Measurements of cellular dimensions were made by a stereological method that provides unbiased estimates.²² These measurements showed that the cell volume is increased in patients with high circulating (and probably also tissue) levels of renin, angiotensin II, and aldosterone, whereas in patients with high circulating levels of aldosterone alone and low levels of renin and angiotensin II, the smooth muscle cell volume (albeit slightly greater) was not significantly different from that observed in patients with essential hypertension and in normotensive subjects. The number of cells per segment length (index of vascular hyperplasia) was similar in the 4 groups of subjects. Therefore, the effect of a pronounced stimulation of the renin-angiotensin-aldosterone system is toward an inward hypertrophic remodeling of the small artery.⁸ This contrasts with the eutrophic remodeling seen in resistance vessels in human essential hypertension and raises the possibility that different treatment regimens may be needed to obtain full regression of vascular structure in the 2 cases; however, this point requires further investigation. The finding that the increased vascular mass in patients with renovascular hypertension is due to cell hypertrophy, and not to hyperplasia, suggests that antihypertensive therapy with blockers of the renin-angiotensin-aldosterone system should be able to directly interfere with the processes leading to an increased production of proteins and cell constituents. On the contrary, regression of cellular hyperplasia might be obtained with drugs stimulating programmed cell death (apoptosis).

Vascular smooth muscle cell hypertrophy may be a direct consequence of the increased activation of the renin-angiotensin-aldosterone system, the hallmark of renovascular hypertension. In fact, it is well known that angiotensin II is involved in the processes that lead to cell growth²³ ; furthermore, aldosterone, per se, seems to possess a profibrotic effect²⁴ and, most probably, growth-promoting effects²⁵ in the vasculature. A possible limitation of the present study is the absence of information about collagen deposition in the vessel wall. Angiotensin II was shown to induce vascular hypertrophy also, which was independent from its effects on blood pressure.^{26 27} On the other hand, it is also possible that the effects of angiotensin II on cardiovascular structure could be mediated, at least in part, by stimulation of the production of endothelin-1,²⁸ which was demonstrated to possess growth-promoting properties. It is also possible that additional neurohumoral factors, besides angiotensin II, endothelin-1, and aldosterone, may have influenced vascular growth. We have not observed any difference in cell number between normotensive subjects and patients with primary or secondary hypertension. However, angiotensin II was previously demonstrated to be able to induce vascular smooth muscle cell replication²⁹ and to stimulate apoptosis.³⁰ Therefore, it is also possible that in renovascular hypertension a cellular hyperplasia may be balanced by apoptosis, which is reportedly enhanced in the large vessels of spontaneously hypertensive rats.³¹ We could not explore this aspect because the apoptosis rate in human subcutaneous small resistance arteries is so low that it is presently impossible to evaluate it with current techniques (eg, terminal deoxynucleotidyl transferase—mediated dUTP nick end-labeling and DNA laddering).

The hemodynamic effect of the increased blood pressure values might be a possible confounding factor in the results obtained in the present study. However, blood pressure, as evaluated by clinical measurements, was not significantly different among the several hypertensive groups. Furthermore, 24-hour noninvasive ambulatory blood pressure monitoring performed in a small subgroup of hypertensive patients (6 with essential hypertension, 5 with primary aldosteronism, and 9 with renovascular hypertension) did not show any difference in average 24-hour blood pressure or in daytime or nighttime blood pressure measurements. Other possible confounders could have been the duration of hypertension and the duration as well as the characteristics of antihypertensive treatment (types of drugs and blood pressure values during treatment). In fact, it was previously demonstrated that different antihypertensive drugs may have different effects on vascular structure.^{32 33 34 35} However, in the present study, the 3 hypertensive groups were also similar regarding these aspects. In particular, the percentage of patients that were previously treated with angiotensin-converting enzyme inhibitors or calcium antagonists were similar in the different groups. Therefore, it is highly improbable that the morphological differences observed could be ascribed to treatment effects.

Morphometric changes found among the different groups could be theoretically ascribed to changes in the mechanical properties of the vessel wall. This did not seem to be the case, in view of the fact that our plot of incremental elastic modulus against wall stress showed no difference between hypertensive patients and normotensive subjects or among the different hypertensive groups. In a previous study, no difference in the passive elastic properties of subcutaneous small arteries between patients with essential hypertension and normotensive subjects¹⁵ was observed, thus suggesting that the altered morphology observed in hypertensive patients is not caused by a change in the elastic characteristics of the wall material. Recently, in a study from Intengan et al,³⁶ a decreased stiffness of wall component was observed in human subcutaneous small arteries of patients with essential hypertension, compared with normotensive subjects, whereas distensibility was similar. These modest discrepancies could be partially ascribed to the different techniques used (pressurized system versus micromyographic technique) or to the characteristics of the patients studied (age and global profile of cardiovascular risk factors).

In conclusion, an inward hypertrophic remodeling due to vascular smooth muscle cell hypertrophy, as evaluated by a direct unbiased method, was observed in the small arteries of patients with renovascular hypertension but not in patients with essential hypertension or primary aldosteronism. Therefore, a pronounced activation of the renin-angiotensin-aldosterone system is associated with vascular smooth muscle cell hypertrophy not only in experimental models of hypertension but also in humans.

	Acknowledgments

 
The authors thank Mette Schandorff and Alessandra Panarotto for technical assistance.

	Footnotes

 
Reprint requests to Enrico Agabiti Rosei, MD, Chair of Internal Medicine, c/o 2^a Medicina, Spedali Civili di Brescia, 25100 Brescia, Italy.

Received July 28, 1999; first decision August 20, 1999; accepted November 16, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Folkow B. Physiological aspects of primary hypertension. Physiol Rev. 1982;63:347–504.

2. Sivertsson R. The hemodynamic importance of structural vascular changes in essential hypertension. Acta Physiol Scand. 1970;343:14–19.

3. Mulvany MJ, Aalkjaer C. Structure and function of small arteries. Physiol Rev. 1990;70:921–971.[Abstract/Free Full Text]

4. Mulvany MJ, Hansen PK, Aalkjaer C. Direct evidence that the greater contractility of resistance vessels in spontaneously hypertensive rats is associated with a narrowed lumen, a thickened media, and an increased number of smooth muscle cell layers. Circ Res. 1978;43:854–864.[Abstract/Free Full Text]

5. Aalkjaer C, Heagerty AM, Petersen KK, Swales JD, Mulvany MJ. Evidence for increased media thickness, increased neural amine uptake, and depressed excitation-contraction coupling in isolated resistance vessels from essential hypertensives. Circ Res. 1987;61:181–186.[Abstract/Free Full Text]

6. Rizzoni D, Castellano M, Porteri E, Bettoni G, Muiesan ML, Agabiti-Rosei E. Vascular structural and functional alterations before and after the development of hypertension in SHR. Am J Hypertens. 1994;7:193–200.[Medline] [Order article via Infotrieve]

7. Heagerty AM, Aalkjaer C, Bund SJ, Korsgaard N, Mulvany MJ. Small artery structure in hypertension: dual process of remodeling and growth. Hypertension. 1993;21:391–397.[Free Full Text]

8. Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty, AM, Korsgaard N, Schiffrin EL, Heistad DD. Vascular remodeling. Hypertension. 1996;28:505–506. Letter.

9. Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension. 1989;13:968–972.[Abstract/Free Full Text]

10. Sterio DC. The unbiased selection of number and sizes of arbitrary particles using the disector. J Microsc. 1984;134:127–136.[Medline] [Order article via Infotrieve]

11. Korsgaard N, Aalkjaer C, Heagerty AM, Izzard AS, Mulvany MJ. Histology of subcutaneous small arteries from patients with essential hypertension. Hypertension. 1993;22:523–526.[Abstract/Free Full Text]

12. Mulvany MJ, Baandrup U, Gundersen HJG. Evidence for hyperplasia in mesenteric resistance vessels of spontaneously hypertensive rats using a three-dimensional disector. Circ Res. 1985;57:794–800.[Abstract/Free Full Text]

13. Korsgaard N, Mulvany MJ. Cellular hypertrophy in mesenteric resistance vessels from renal hypertensive rats. Hypertension. 1988;12:162–167.[Abstract/Free Full Text]

14. Rizzoni D, Porteri E, Castellano M, Bettoni G, Muiesan ML, Muiesan P, Giulini SM, Agabiti Rosei E. Vascular hypertrophy and remodeling in secondary hypertension. Hypertension. 1996;28:785–790.[Abstract/Free Full Text]

15. Thybo NK, Mulvany MJ, Jastrup B, Nielsen H, Aalkjaer C. Some pharmacological and elastic characteristics of isolated subcutaneous small arteries from patients with essential hypertension. J Hypertens. 1996;14:993–998.[Medline] [Order article via Infotrieve]

16. Mulvany MJ. Biophysical aspects of resistance vessels studied in spontaneous and renal hypertensive rats. Acta Physiol Scand. 1988;133(suppl 571):129–138.

17. Aalkjaer C, Eiskjaer H, Mulvany MJ, Jespersen B, Kjaer T, Sorensen SS, Pedersen EB. Abnormal structure and function of isolated subcutaneous resistance vessels from essential hypertensive patients despite antihypertensive treatment. J Hypertens. 1989;7:305–310.[Medline] [Order article via Infotrieve]

18. Mulvany MJ, Halpern W. Contractile properties of small resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977;41:19–26.[Free Full Text]

19. Rizzoni D, Castellano M, Porteri E, Bettoni G, Muiesan ML, Agabiti Rosei E. Delayed development of hypertension after short-term nitrendipine treatment. Hypertension. 1994;24:131–139.[Abstract/Free Full Text]

20. Rizzoni D, Castellano M, Porteri E, Bettoni G, Muiesan ML, Cinelli A, Agabiti Rosei E. Effects of low and high doses of fosinopril on the structure and function of resistance arteries. Hypertension. 1995;26:118–123.[Abstract/Free Full Text]

21. Korsgaard N, Christensen KL, Mulvany MJ. Cellular morphology in mesenteric resistance vessels from antihypertensive treated spontaneously hypertensive rats. In: Smiths JFM. Pharmacology of Cardiac and Vascular Remodelling. Darmstadt, Germany: Steinkopff Verlag; 1991:33–41.

22. Baandrup U, Gundersen HJG, Mulvany MJ. It is possible to solve the problem: hypertrophy/hyperplasia of smooth muscle cells in the vessel wall of hypertensive subjects? Adv Appl Microcirc.. 1985;8:122–128.

23. Schelling P, Fischer H, Ganten D. Angiotensin and cell growth: a link to cardiovascular hypertrophy? J Hypertens. 1991;9:3–15.[Medline] [Order article via Infotrieve]

24. Weber KT, Sun Y, Guarda E. Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension. 1994;23(pt 2):869–877.

25. Schneider M, Ulsenheimer A, Christ M, Wehling M. Nongenomic effects of aldosterone on intracellular calcium in porcine endothelial cells. Am J Physiol. 1997;272(pt 1):E616–E620.

26. Griffin SA, Brown WCB, MacPherson F, McGrath JC, Wilson VG, Korsgaard N, Mulvany MJ, Lever AF. Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism. Hypertension. 1991;17:626–635.[Abstract/Free Full Text]

27. Black MJ, Bertram JF, Campbell JH, Campbell GR. Angiotensin II induces cardiovascular hypertrophy in perindopril-treated rats. J Hypertens. 1995;13:683–692.[Medline] [Order article via Infotrieve]

28. Schiffrin EL, Deng LY, Sventek P, Day R. Enhanced expression of endothelin-1 gene in severe human essential hypertension. J Hypertens. 1997;15:57–63.[Medline] [Order article via Infotrieve]

29. Su EJ, Lombardi DM, Wiener J, Daemen MJ, Reidy MA, Schwartz SM. Mitogenic effect of angiotensin II on rat carotid artery and type II or III mesenteric microvessels but not type I mesenteric microvessels is mediated by endogenous basic fibroblast growth factor. Circ Res. 1998;82:321–327.[Abstract/Free Full Text]

30. Yamada T, Horiuchi M, Dzau VJ. Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci U S A.. 1996;93:156–160.

31. Sharifi AM, Schiffrin EL. Apoptosis in vasculature of spontaneously hypertensive rats: effect of an angiotensin converting enzyme inhibitor and a calcium channel antagonists. Am J Hypertens. 1998;11:1109–1116.

32. Schiffrin EL, Deng LY, Larochelle P. Effects of a ß-blocker or a converting enzyme inhibitor on resistance arteries in essential hypertension. Hypertension. 1994;23:83–91.[Abstract/Free Full Text]

33. Thybo NK, Stephens N, Cooper A, Aalkjaer C, Heagerty AM, Mulvany MJ. Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension. Hypertension. 1995;25(pt 1):474–481.

34. Rizzoni D, Muiesan ML, Porteri E, Castellano M, Zulli G, Bettoni G, Salvetti M, Monteduro C, Agabiti-Rosei E. Effect of long-term antihypertensive treatment with lisinopril on resistance arteries in hypertensive patients with left ventricular hypertrophy. J Hypertens. 1997;15:197–204.[Medline] [Order article via Infotrieve]

35. Schiffrin EL, Deng LY. Structure and function of resistance arteries of hypertensive patients treated with a beta blocker or a calcium channel antagonist. J Hypertens. 1996;14:1237–1244.[Medline] [Order article via Infotrieve]

36. Intengan HD, Deng LY, Li JS Schiffrin E. Mechanics and composition of human subcutaneous resistance arteries in essential hypertension. Hypertension. 1999;33(pt II):569–574.

This article has been cited by other articles:

				F. Feihl, L. Liaudet, B. I. Levy, and B. Waeber Hypertension and microvascular remodelling Cardiovasc Res, May 1, 2008; 78(2): 274 - 285. [Abstract] [Full Text] [PDF]

				S. Heeneman, J. C. Sluimer, and M. J.A.P. Daemen Angiotensin-Converting Enzyme and Vascular Remodeling Circ. Res., August 31, 2007; 101(5): 441 - 454. [Abstract] [Full Text] [PDF]

				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]

				A. M. Briones, F. E. Xavier, S. M. Arribas, M. C. Gonzalez, L. V. Rossoni, M. J. Alonso, and M. Salaices Alterations in structure and mechanics of resistance arteries from ouabain-induced hypertensive rats Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H193 - H201. [Abstract] [Full Text] [PDF]

				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]

				M. Puato, E. Faggin, E. Favaretto, B. Bertipaglia, M. Rattazzi, D. Rizzoni, G. P. Gamba, S. Sartore, E. A. Rosei, A. C. Pessina, et al. Prevalence of Fetal-Type Smooth Muscle Cells in the Media of Microvessels From Hypertensive Patients Hypertension, August 1, 2004; 44(2): 191 - 194. [Abstract] [Full Text] [PDF]

				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]

				I. Gouni-Berthold, C. Seul, Y. Ko, J. Hescheler, and A. Sachinidis Gangliosides GM1 and GM2 Induce Vascular Smooth Muscle Cell Proliferation via Extracellular Signal-Regulated Kinase 1/2 Pathway Hypertension, November 1, 2001; 38(5): 1030 - 1037. [Abstract] [Full Text] [PDF]

				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]

				C. Vecchione, L. Fratta, D. Rizzoni, A. Notte, R. Poulet, E. Porteri, G. Frati, D. Guelfi, V. Trimarco, M. J. Mulvany, et al. Cardiovascular Influences of {alpha}1b-Adrenergic Receptor Defect in Mice Circulation, April 9, 2002; 105(14): 1700 - 1707. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rizzoni, D. Articles by Rosei, E. A. Search for Related Content PubMed PubMed Citation Articles by Rizzoni, D. Articles by Rosei, E. A. Related Collections Hypertension - basic studies Smooth muscle proliferation and differentiation Mechanism of atherosclerosis/growth factors