Changes in skin angiotensin II receptors in rats during wound healing

Kimura, Birgitta; Sumners, Colin; Phillips, M. Ian

doi:10.1016/0006-291x(92)91308-d

Cited by 80 publications

(56 citation statements)

References 26 publications

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“…It has been reported that adult rat skin contains predominantly AT1R (18) and that Ang II accelerates the closure of thermal injuries and full-thickness dermal lesions in these animals. In addition to the contribution of exogenous Ang II to wound repair, studies have shown that increased levels of Ang II and ATRs are produced at the site of wound .…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that adult rat skin contains predominantly AT1R (18) and that Ang II accelerates the closure of thermal injuries and full-thickness dermal lesions. Both of these responses are associated with the enhancement of several physiological processes necessary for skin wound repair, such as the proliferation of keratinocytes and the production of extracellular matrix (19 -21).…”

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confidence: 99%

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A Novel Function of Angiotensin II in Skin Wound Healing

Yahata

Shirakata

Tokumaru

et al. 2006

Journal of Biological Chemistry

124

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The role of angiotensin II (Ang II) in the control of systemic blood pressure and volume homeostasis is well known and has been extensively studied. Recently, Ang II was suggested to also have a function in skin wound healing. In the present study, the in vivo function of Ang II in skin wound healing was investigated using Ang II type 1 receptor (AT1R) knock-out mice. Wound healing in these mice was found to be markedly delayed. Keratinocytes and fibroblasts play important roles in wound healing, and thus the effect of Ang II on the migration of these cells was examined. Ang II stimulated keratinocyte and fibroblast migration in a dose-dependent manner. It has been reported that G protein-coupled receptor (GPCR) activation induces epidermal growth factor (EGF) receptor (EGFR) transactivation through the shedding of heparin-binding EGF-like growth factor (HB-EGF). As AT1R is a GPCR, it was hypothesizedthat Ang II-induced keratinocyte and fibroblast migration is mediated by EGFR transactivation. Ang II induced EGFR phosphorylation, which was inhibited by an AT1R antagonist, HB-EGF neutralizing antibody, and an HB-EGF antagonist in both keratinocytes and in fibroblasts. Moreover, Ang II-induced migration of keratinocytes and fibroblasts was also prevented by these inhibitors. Taken together, these findings clearly demonstrate, for the first time, that Ang II plays an important role in skin wound healing and that it functions by accelerating keratinocyte and fibroblast migration in a process mediated by HB-EGF shedding.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A Novel Function of Angiotensin II in Skin Wound Healing

Yahata

Shirakata

Tokumaru

et al. 2006

Journal of Biological Chemistry

124

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“…These cells express both AT1 and AT2 receptors (Tsutsumi et al, 1991;Johnson & Aguilera, 1991), AT2 receptors predominating on foetal skin fibroblasts. In the rat, however, there is a dramatic decrease in angiotensin receptors on skin fibroblasts following birth (Millan et al, 1989), and in the adult rat, dermal angiotensin receptors are predominantly of the AT1 subtype (Kimura et al, 1992 (Millan et al, 1989) and their possible role in synovial hypertrophy in inflammatory arthritis deserves further investigation.…”

Section: Introductionmentioning

confidence: 99%

AT₁ receptor characteristics of angiotensin analogue binding in human synovium

Walsh

Suzuki²,

Knock

et al. 1994

British J Pharmacology

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Angiotensin II (AII) reduces blood flow, modulates vascular remodelling and is a growth factor. Human inflammatory arthritides are characterized by synovial hypoperfusion, hypoxia and proliferation. We aimed to localize and characterize receptors for AII in human synovium. We used quantitative in vitro receptor autoradiography with [125I]‐(Sar1, Ile8)AII and [125I]‐AII on human synovium from patients with chondromalacia patellae, osteoarthritis and rheumatoid arthritis. [125I]‐(Sar1, Ile8)AII and [125I]‐AII bound to similar sites on synovial blood vessels, lining cells and stroma. Binding to microvessels (< 100 μm diameter) was more dense than to arteriolar media, and vascular binding was more dense than that to lining cells and stroma. Microvessels and arterioles which displayed angiotensin converting enzyme‐like immunoreactivity also displayed specific binding of [125I]‐(Sar1, Ile8)AII. Specific binding of [125I]‐(Sar1, Ile8)AII to each structure was completely inhibited by 10 μm dithiothreitol and was inhibited by unlabelled ligands with the rank order of potency (Sar1, Ile8)AII > AII > losartan = SKF108566 > PD123319 indicating an AT1 subclass of angiotensin receptor. GTPγS (1 μm) abolished specific binding of [125I]‐AII and abolished the high affinity component of the binding inhibition curve for AII against [125I]‐(Sar1, Ile8)AII, indicating G protein coupling. The distribution of [125I]‐(Sar1, Ile8)AII binding sites was similar in all disease groups and no significant differences in binding densities, affinities or specificities were observed between disease groups. Locally generated AII may act on synovial AT1 receptors to modulate synovial perfusion and growth. Specific AT1 receptor antagonists should help elucidate the role of angiotensins in human arthritis.

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“…This effect could be suppressed by an angiotensin receptor I antagonist [17]. In rats, the angiotensin receptor II was overexpressed on day 3 after wounding [18, 19]. Furthermore, it was shown that candesartan inhibits the angiotensin II-stimulated migration of keratinocytes [20].…”

Section: Introductionmentioning

confidence: 99%

Side Effects of Frequently Used Antihypertensive Drugs on Wound Healing in vitro

Besser

Terberger

Bachmann

et al. 2019

Skin Pharmacol Physiol

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Background: The number of patients who has a daily intake of antihypertensive drugs is rising, due to an also rising prevalence of lifestyle diseases. Interestingly, knowledge about effects of these drugs in terms of wound healing is low. Objective: Based on a few differing studies, the idea arose that antihypertensives may have side effects on wound healing. Methods: Five antihypertensive drugs from different substance classes (metoprolol, amlodipine, ramipril, hydrochlorothiazide, candesartan) were investigated, in terms of possible impacts on cell metabolism and migration of human skin fibroblasts and keratinocytes. Additionally, histological and immunohistochemical analyses were performed in a 3-dimensional (3D) wound model addressing the influence on regeneration processes, such as cell migration, metabolic activity, apoptosis and epidermal thickness. Results: Hydrochlorothiazide and ramipril exerted inhibiting effects in nearly all analyses, interestingly, in serum equivalent doses. In contrast, candesartan and amlodipine induced slight positive effects in 2D as well as in 3D models. The previously described positive effects of β-blockers could only partially be confirmed by metoprolol. Antihypertensive drugs affected fibroblasts more than keratinocytes – whether positively or negatively. Conclusion: Antihypertensive drugs have an influence on keratinocytes and fibroblasts; they are not neutral. Candesartan has the most positive effects on skin cells. For angiotensin-converting enzyme inhibitors and thiazide diuretics, wound healing in a 3D model is delayed. β-Receptor blockers seem to improve wound healing to a small extent just like calcium channel blockers. These results should be evaluated in a clinical trial to verify their clinical relevance.

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Changes in skin angiotensin II receptors in rats during wound healing

Cited by 80 publications

References 26 publications

A Novel Function of Angiotensin II in Skin Wound Healing

A Novel Function of Angiotensin II in Skin Wound Healing

AT₁ receptor characteristics of angiotensin analogue binding in human synovium

Side Effects of Frequently Used Antihypertensive Drugs on Wound Healing in vitro

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Changes in skin angiotensin II receptors in rats during wound healing

Cited by 80 publications

References 26 publications

A Novel Function of Angiotensin II in Skin Wound Healing

A Novel Function of Angiotensin II in Skin Wound Healing

AT1 receptor characteristics of angiotensin analogue binding in human synovium

Side Effects of Frequently Used Antihypertensive Drugs on Wound Healing in vitro

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AT₁ receptor characteristics of angiotensin analogue binding in human synovium