Increased Collagen Synthesis in Blood Vessels of Hypertensive Rats and Its Reversal by Antihypertensive Agents

Ooshima, Akira; Fuller, George C.; Cardinale, George J.; Spector, Sydney; Udenfriend, Sidney

doi:10.1073/pnas.71.8.3019

Cited by 144 publications

(50 citation statements)

References 24 publications

(19 reference statements)

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“…Based on our findings, we hypothesize that elderly patients with isolated systolic hypertension whose large arteries are stiff, and in whom stiffening is associated with increased fibrosis should benefit to a high degree from ACE-I-based antihypertensive treatment. However, further intervention studies including patients with isolated systolic, and systolo-diastolic hypertension, should elucidate this issue in a prespecified manner ( PIIINP found to be related with increased stiffness (PWV) in periand postmenopausal women with SBP X160 mmHg Type III collagen increased in vessels in hypertensives 9 Left ventricular hypertrophy and stiffness related to increased serum concentrations of type I and III collagen metabolites 20 No relation between stiffness and PICP found Positive relation between PWV and PICP in hypertensives. Both PWV and PICP decrease upon treatment with an ACE-I 29 PIIINP, N-terminal procollagen type III propeptide; PICP, C-terminal procollagen type I propeptide; PWV, pulse wave velocity; SBP, systolic blood pressure.…”

Section: Discussionmentioning

confidence: 99%

The relationship between pulse wave velocity and indexes of collagen synthesis in hypertensive patients, according to the level of systolic blood pressure

et al. 2005

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Vascular stiffening, a process responsible for the development of isolated systolic hypertension, depends on dysregulation of collagen-elastine production and arrangement, yet it is not known whether the effect is uniform throughout wide blood pressure (BP) range. To check whether arterial stiffness is similarly related to increased fibrotic remodelling, in patients with systolic blood pressure (SBP) above and below 160 mmHg. Consecutive peri-and postmenopausal female outpatients treated for hypertension and free from other disorders interfering with fibrotic processes, had their BP, pulse wave velocity (PWV), and collagen (N-terminal procollagen type III propeptide (PIIINP); C-terminal procollagen type I propeptide-(PICP)) measured. The average age of 100 women was 71.8710.5 years, BP was 145/83725/15 mmHg, pulse pressure 63717 mmHg, and mean blood pressure (MBP) 104717 mmHg. PWV was 12.973.6 m/s and was significantly higher among 30 patients with SBP of X160 mmHg. PIIINP averaged 4.671.6 ng/ml and PICP 142.2747.0 ng/ml. In the low SBP (o160 mmHg) group there was no relationship between PWV and collagen concentrations. However, in the X160 mmHg group there was significant correlation between PWV and PIIINP concentration. The relationship held significant after adjustment for age, and BP components. Our result can help explaining the results of recent intervention trials where older patients tended to benefit more from potentially antifibrotic drugs (ACE-I), whereas those with compliant arteries tend to benefit from diuretics.

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Section: Discussionmentioning

confidence: 99%

The relationship between pulse wave velocity and indexes of collagen synthesis in hypertensive patients, according to the level of systolic blood pressure

et al. 2005

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“…At the times indicated, the animals were killed with ether and the tail tendon, skin from the abdominal area, the aorta, and the mesenteric artery were removed. The vascular tissues were prepared as previously described (1). Hair and subcutaneous fat were removed from the skin with a scalpel and the tendon was carefully separated from surrounding connective tissue.…”

Section: Methodsmentioning

confidence: 99%

Increased turnover of arterial collagen in hypertensive rats.

Nissen¹,

Cardinale²,

Udenfriend³

1978

Proc. Natl. Acad. Sci. U.S.A.

174

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The turnover of total collagen in several tissues of 12-week-old normotensive and hypertensive rats was estimated by using tritium-labeled proline as a precursor. The effect of reutilization of the label was minimized by treatment with large doses of unlabeled proline subsequent to administering the radioactive imino acid. The collagen from skin, tail tendon, aorta, and mesenteric artery in normotensive animals had a half-life of about 60-70 days. In hypertensive animals the half-lives of skin and tail tendon collagen were unchanged but the half-lives of collagen in the aorta and mesenteric artery were reduced to 17 days.In previous studies from this laboratory we reported that hypertension in rats leads to an increased synthesis and deposition of collagen in arteries (1) and microvessels (2). In one set of experiments, treatment of hypertensive rats with f-aminopropionitrile, an inhibitor of collagen crosslinking, resulted in a lowering of the blood pressure within 3 weeks (3). If collagen deposition itself leads to a maintenance of the elevated pressure as we have proposed (3), then this reversal in such a short time may indicate that in hypertension collagen breakdown as well as synthesis may be accelerated. To investigate this possibility, we set about to measure the decay in specific activity of protein-bound hydroxyproline (collagen) after rats were labeled with L-[2,3-3H]proline. Many other investigators have attempted to measure collagen turnover using radioactive amino acids (4-9); however, no correction was made for reutilization of the labeled amino acid that was used. In this report we have utilized an in vivo pulse-chase experiment to minimize the problem of reutilization and have been able to estimate the turnover of collagen in several tissues of normal and hypertensive rats. Normotensive rats (12-weeks-old) with an average body weight of 373 g were kept in disposable cages in a hood. DOCA/salt hypertension was produced in uninephrectomized 6-week-ole male Wistar rats by twice weekly subcutaneous injection of DOCA (5 mg per rat) (10, 11). Rats were maintained on the standard diet and allowed free access to drinking water containing 1% NaCl. After 6 weeks of treatment their average blood pressure was 200 mm Hg (1 mm Hg = 133 Pa) and their average body weight was 416 g. During the experiments, the normotensive animals gained 120 g in 53 days and 250 g in 111 days, while the hypertensives gained 90 g in 53 days. Of the twenty rats started on the DOCA/salt regimen, five died from respiratory infections and three others could not be used because they were also infected. For this reason only three time points could be measured for the hypertensive group. Blood pressure was monitored weekly by the tail cuff microphone method with an instrument made by Hoffmann-La Roche & Co., Basel, Switzerland. MATERIALS AND METHODSBlood was obtained by either cardiac puncture or tail vein bleeding. Serum proteins were precipitated by the addition of 3 ml of 10% trichloroacetic acid per ml of serum and removed ...

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“…In normal arteries, fibrillar collagens I and III are major constituents of the intima, media, and adventitia, whereas types I, III, IV, and V are in endothelial and SMC basement membranes. 58 There are early reports 47,48 of increased collagen synthesis in the arterial wall in hypertension that occurred globally in SHR and DOCA-salt rat aortae, mesenteric arteries, cerebral microvessels, pial arteries, and basilar arteries. Collagen accumulation may not follow synthesis and may be bed specific, as it occurs in coronary arteries 49 but less consistently in aortae of SHR 50 or DOCA-salt rats, 51 although recent studies report increases in collagen III but not collagen I in Japanese and Lyon SHR strains.…”

Section: Vascular Fibrosismentioning

confidence: 99%

Vascular Remodeling in Hypertension

2001

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Abstract-Remodeling of large and small arteries contributes to the development and complications of hypertension. The focus of this review is some of the mechanisms involved in the remodeling of small arteries in hypertension. In hypertension, changes in small artery structure are basically of 2 kinds: (1) inward eutrophic remodeling, in which outer and lumen diameters are decreased, media/lumen ratio is increased, and cross-sectional area of the media is unaltered; and (2) hypertrophic remodeling, in which the media thickens to encroach on the lumen, resulting in increased media cross-sectional area and media/lumen ratio. Growth, apoptosis, inflammation, and fibrosis contribute to vascular remodeling in hypertension. Apoptosis is gene-regulated cell death, with minimal membrane disruption and inflammation, that counters cell proliferation and fine-tunes developmental growth. Apoptosis has been reported in hypertension to be both increased and decreased in different tissues, including blood vessels. Inflammation, which may be low grade, probably plays an important role in triggering fibrosis in cardiovascular disease and hypertension. Vascular fibrosis entails accumulation of collagen, fibronectin, and other extracellular matrix components in the vessel wall and is an important aspect of extracellular matrix remodeling in hypertension. Associated with this, there may be increases in cell-matrix attachment sites (integrins) and changes in their topographical localization that may modulate arterial structure. Imbalance in matrix metalloproteinase/tissue inhibitors of metalloproteinases may contribute to alteration in collagen turnover and extracellular matrix remodeling. Chronic vasoconstriction may lead to embedding of the contracted vessel structure in a remodeled extracellular matrix, contributing to the inward remodeling of the blood vessel as smooth muscle cells are rearranged around a smaller lumen. The resulting remodeling of small arteries may initially be adaptive, but eventually it becomes maladaptive and compromises organ function, contributing to cardiovascular complications of hypertension. Key Words: arteries Ⅲ apoptosis Ⅲ inflammation Ⅲ fibrosis Ⅲ collagen Ⅲ muscle, smooth I n hypertension, resistance arteries undergo eutrophic and/or hypertrophic remodeling. 1 In inward eutrophic remodeling, outer and lumen diameters are reduced, media cross-sectional area is unaltered, and media/lumen ratio is increased, without stiffening. Spontaneously hypertensive (SHR) 1,2 and 2-kidney, 1-clip Goldblatt 3 rats, as well as mild essential hypertensive patients, 3,4 exhibit predominantly inward eutrophic remodeling. When media growth encroaches on the lumen to increase the media/lumen ratio, the change has been called hypertrophic remodeling. It predominates in severe hypertension, such as in deoxycorticosterone acetate (DOCA)-salt rats, 5 1-kidney, 1-clip (1K1C) Goldblatt rats, 6 -8 Dahl salt-sensitive rats, 9 and humans with secondary hypertension. 10 Growth, apoptosis, inflammation, and fibrosis are all mech...

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Increased Collagen Synthesis in Blood Vessels of Hypertensive Rats and Its Reversal by Antihypertensive Agents

Cited by 144 publications

References 24 publications

The relationship between pulse wave velocity and indexes of collagen synthesis in hypertensive patients, according to the level of systolic blood pressure

The relationship between pulse wave velocity and indexes of collagen synthesis in hypertensive patients, according to the level of systolic blood pressure

Increased turnover of arterial collagen in hypertensive rats.

Vascular Remodeling in Hypertension

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