Summary
Background Angiotensin AT1 and AT2 receptors are expressed in human skin. Furthermore, AT2 receptors have been reported to be upregulated during tissue repair and remodelling in various noncutaneous human tissues.
Objectives Detection of alterations in angiotensin II receptor expression during wound healing in human skin.
Methods Three models were employed. (i) Primary human keratinocytes were razor scraped in culture flasks and alterations in the expression of angiotensin receptor mRNA determined by semiquantitative reverse transcription–polymerase chain reaction for 1–12 h thereafter. (ii) Early wound healing (48 h after cutting) was studied in punch biopsies from human skin ex vivo by means of immunohistochemical staining using polyclonal antibodies against the AT1 or AT2 receptor. (iii) In vivo wound healing was studied in sections of human cutaneous scars by immunohistochemistry to determine receptor expression early (2 days) and late (2 weeks−3 months) after surgery.
Results In all experimental settings, an upregulation of both receptor subtypes was noticed after wounding. Immunohistochemically stained skin sections showed a stronger expression of AT2 than of AT1 receptors within the area of scarring. Enhanced receptor expression was detectable as early as 24 h after injury and lasted for up to 3 months.
Conclusions From these data, we conclude that angiotensin AT1 and AT2 receptors are upregulated in human cutaneous wounds, giving further support to the concept that angiotensin II plays a role even at an early stage during cutaneous wound healing.
Objectives AT 2 R defi ciency exacerbates atherosclerotic progression in ApoE (-/-) mice. Because AT 2 Rs are low/undetectable in wild-type (WT) C57BL/6 aortas we hypothesize that ApoE regulates vascular AT 2 Rs.
MethodsWe measured AT 2 Rs (using quantitative-immunofl uorescence) in aortic arch vascular smooth muscle (VSMC) and endothelial cell (EC) layers and mean arterial blood pressure (MAP) in anesthetized mice. Nine-week-old ApoE (-/-) and WT mice were fed a low (LC) or high cholesterol (HC) diet for 1 week. Animals were administered vehicle or Ang II (12 g/kg/hr), with or without PD123319 (10 mg/kg/day) (AT 2 R antagonist) for 7 days.
ResultsIn LC/ApoE (-/-) vs. WT mice, VSMC and EC AT 2 R was 80-and 26-fold higher (P Ͻ 0.001). HC increased serum cholesterol ~2-fold (P Ͻ 0.001) and decreased VSMC AT 2 R levels 9.5-fold (P Ͻ 0.01) in ApoE (-/-) mice. Low-dose Ang II infusion, which was without effect in LC/WT mice decreased MAP by 15% in LC/ApoE (-/-) (79 Ϯ 2 vs. 67 Ϯ 3 mmHg, vehicle vs. Ang II, respectively; n ϭ 10/gp., P Ͻ 0.01) but not HC/ ApoE (-/-) mice (82 Ϯ 3 vs. 80 Ϯ 2 mmHg vehicle vs. Ang II, respectively; n ϭ 7-11/gp.). A study of vasodilator mechanisms indicated that lowdose Ang II caused a ~6-fold increase in VSMC, but not EC, PPAR-␥ (P Ͻ 0.001) in LC/ApoE (-/-) mice; both VSMC and EC phospho-nitric oxide synthase were not signifi cantly changed. These effects were blocked by PD123319.Methods Male spontaneously hypertensive rats (SHRs) were divided into six groups and treated transiently with three injections of vehicle or AT1 receptor vaccine (0.1 mg) at age 4, 6 and 8 weeks, or continuously with candesartan cilexetil (0.1 mg/kg/day) or hydralazine hydrochloride (5 mg/kg/day), then administered NG-nitro-Larginine methyl ester (L-NAME) from age 18 to 21 weeks to induce renal injury.
ResultsVaccination against the AT1 receptor caused a signifi cant increase in AT1 receptor titers, and a sustained decrease in BP. L-NAME
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