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Early Endothelial Dysfunction Severely Impairs Skin Blood Flow

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Early Endothelial Dysfunction Severely Impairs Skin Blood Flow Early Endothelial Dysfunction Severely Impairs Skin Blood Flow Response to Local Pressure Application in Streptozotocin-Induced Diabetic Mice Dominique Sigaudo-Roussel, Claire Demiot, Be´renge`re Fromy, Audrey Koı¨tka, Georges Lefthe´riotis, Pierre Abraham, and Jean Louis Saumet Pressure-induced vasodilation (PIV) is a mechanism al. (2) demonstrated a major role for vasodilators such as whereby skin blood flow increases in response to pro- the calcitonin gene–related peptide and endothelial vaso- gressive locally applied pressure. Skin blood flow in dilators such as nitric oxide (NO) and prostaglandins in response to applied pressure decreased early in diabetic animal studies. In a recent study, we observed in diabetic patients as a result of vascular and/or neural impair- patients an early decrease of skin blood flow in response ment. This study was designed to determine the effect of to locally applied pressure that could be involved in the vascular changes on PIV in 1-week streptozotocin-in- development of diabetic ulceration (3). However, it was duced diabetic mice. We assessed cutaneous microvas- cular response to local increasing pressure application unclear whether skin blood flow alteration during diabetes measured by laser Doppler flowmetry (LDF) and endo- depends directly on vascular and/or neural alterations. thelium-dependent and -independent vasodilation by Diabetes through hyperglycemia is widely known to be iontophoretic delivery of acetylcholine and sodium ni- a major factor that leads to microvascular and neural troprusside and sciatic motor nerve conduction velocity complications (4). Indeed, hyperglycemia-induced end- and morphometry. In control mice, LDF increased 34% organ damage in diabetes is associated with increased flux from baseline to 0.2 kPa external pressure, showing PIV of glucose through 1) the polyol metabolic pathway response. In contrast, diabetic mice had no LDF in- (5,6), 2) accumulation of advanced glycation end products crease in response to progressive external pressure. Moreover, after iontophoretic delivery of acetylcholine, (7,8), 3) increased oxidative stress (9,10), and 4) activation endothelium-dependent vasodilation was largely atten- of the protein kinase C pathway (11,12). However, the uated in diabetic mice (25%) compared with control pathogenesis of the vascular complications of diabetes is mice (81%), whereas vasodilation to sodium nitroprus- controversial (13). Several studies in experimental animal side was not different between groups. Nerve function models of diabetes and in human type I and II diabetic as assessed by sciatic nerve conduction velocity and patients revealed impaired endothelium-dependent re- morphometry did not differ between groups. These find- laxation (14,15). However, many in vitro studies have ings suggest that endothelial impairment is sufficient to reported unaltered or enhanced endothelium-dependent severely alter PIV response, which seems to be highly sensitive to endothelial nitric oxide levels. PIV suppres- relaxation (16,17). In addition to these vascular observa- sion could favor diabetes complications such as diabetic tions, Coppey et al. (18) reported as early as 1 week of foot ulcers. Diabetes 53:1564–1569, 2004 diabetes in rats a sciatic nerve blood flow reduction that preceded the slowing of motor nerve conduction velocity (MNCV). Therefore, it seems that vascular dysfunction may be a major factor in the development of diabetic e recently reported a mechanism that allows neuropathy. Indeed, there is evidence that progressive skin blood flow to increase in response to microangiopathy contributes to progressive loss of periph- progressive locally applied pressure in hu- eral and later central neurologic function (19). However, Wmans (1) and rats (2). The pressure applied clinical trials using specific inhibitors of various biochem- is a nonpainful stimulation, but we showed that pres- ical pathways activated by hyperglycemia have shown sure-induced vasodilation (PIV) involved nerve C fibers, modest improvements in neurologic symptoms (20,21). It because it disappeared after chronic treatment with cap- therefore seems to be of importance to focus on early saicin in animals and humans (1,2). In addition, Fromy et vascular alteration, because preventing vascular dysfunc- tion could delay the appearance of diabetic neuropathy. This study was designed to develop a diabetic mouse From the Laboratoire de Physiologie, Faculte´deMe´decine d’Angers, Angers, model that exhibits vascular but not neuropathic changes France. Address correspondence and reprint requests to Prof. Jean Louis Saumet, to study the microvascular response 1) to local pressure Laboratoire de Physiologie, Faculte´deMe´decine d’Angers, 49045 Angers increase and 2) to endothelium-dependent and -indepen- cedex, France. E-mail: [email protected]. Received for publication 23 October 2003 and accepted in revised form dent vasodilators. Nerve function was assessed by sciatic 1 March 2004. nerve conduction velocity and morphometry to verify its ACh, acetylcholine; LDF, laser Doppler flowmetry; MABP, mean arterial integrity. We hypothesized that vascular dysfunction that blood pressure; MNCV, motor nerve conduction velocity; PIV, pressure- induced vasodilation; STZ, streptozotocin. occurs early in diabetes could be sufficient to alter the PIV © 2004 by the American Diabetes Association. response. 1564 DIABETES, VOL. 53, JUNE 2004 D. SIGAUDO-ROUSSEL AND ASSOCIATES RESEARCH DESIGN AND METHODS TABLE 1 Male Swiss mice (20–30 g) were kept on a 12/12-h light/dark cycle with food Body weight and blood glucose and fructosamine levels and water available ad libitum. The present investigation was performed in accordance with the guiding principles in the care and use of animals. Body Blood glucose Fructosamine Diabetes was induced by a single intraperitoneal injection of streptozotocin Animals weight (g) (mg/dl) (␮mol/l) (STZ; 200 mg/kg; Sigma) in citrate buffer (pH 4.5) during the fasting state. Control (n ϭ 10) 31 Ϯ 1 161 Ϯ 7 167 Ϯ 9 Control animals received equivalent doses of the citrate buffer solution. ϭ Ϯ Ϯ Ϯ Hyperglycemia occurred 2 days after STZ injection and was verified using an Diabetic (n 9) 22 1* 495 32† 343 23† Accu-Check Active glucometer (Roche, Lyon, France). We considered mice to *P Ͻ 0.01; †P Ͻ 0.001 vs. control. be diabetic when blood glucose was Ն16 mmol/l (normal 5–8 mmol/l), and only mice with blood glucose Ն16 mmol/l both on the second day and 1 week the M-wave (compound muscle action potential) from the tibial-innervated after the STZ injection were included in the experimental diabetic group. dorsal interossei foot muscles. During recording, the temperature of the site Three studies were performed on the diabetic group 1 week after STZ surrounding the nerve was kept constant at 37°C. treatment. Study 1 examined the microvascular response to local pressure Morphometric analysis. The right sciatic nerves were removed and fixed in increase. Study 2 evaluated the endothelium-dependent and -independent 4% glutaraldehyde in 0.1 mol/l phosphate buffer (pH 7.4) overnight at 4°C, and function. Study 3 was concerned with measurements of sciatic nerve function then washed in 0.1 mol/l phosphate buffer. These fixed samples were postfixed and structure as the MNCV and nerve morphometry. in 2% osmium tetroxide in phosphate buffer, dehydrated through an ascending For presenting a hairless area for the skin laser Doppler flow measure- series of ethanol concentrations, embedded in Epon, and polymerized. One- ments, local pressure application, and iontophoretic application, hair from the micron-thick semithin transverse nerve sections were stained with toluidine blue. top of the skull to the back of the animals was removed with a depilatory Morphometric analysis was performed using a computer-assisted image lotion. This was performed 2 days before the experiments to prevent skin analysis (Qwin, Leı¨ca, France) allowing for the determination of myelinated irritation during the experiment from confounding the results. fiber number and size. All counting was duplicated by two different micros- For the experiments, animals were anesthetized by intraperitoneal injec- copists who were blinded to the animal group, and results were averaged. tion of thiopental sodium (65 mg/kg). The level of anesthesia was determined Data analysis. The reproducibility of each technique was first evaluated in by testing eye reflexes and tail pinch. At the end of each experiment, animals healthy nontreated mice using the coefficient of variation. The techniques were killed by an overdose of thiopental. used in study 1 (PIV assessment), in study 2 (ACh and SNP iontophoretic Study 1: assessment of PIV. Microvascular responses to local pressure in deliveries), and in study 3 (MNCV) had coefficient of variation of 0.24 (139 Ϯ ϭ ϭ control (n 10) and diabetic (n 9) mice were measured by laser Doppler 33 arbitrary units [au], mean Ϯ SD), 0.41 (59 Ϯ 24%, ACh), 0.43 (58 Ϯ 25%, flowmetry (LDF). This method was described by Fromy et al. (2) using a SNP), and 0.25 (51 Ϯ 13 m/s), respectively. The power of the study was 95%. weighbridge that was adapted to hold a laser Doppler probe at one end Unpaired t test was used to evaluate the significance between the diabetic and (PF415; Periflux, Perimed, Sweden). The probe was connected to a laser control groups. To test for significant differences among groups, we per- Doppler flowmeter (PF5000 Master; Periflux). formed one-way ANOVA with Dunnett’s multiple comparison over the base- After general anesthesia, animals were settled in an incubator (MMS, line period. The results are presented as mean Ϯ SE, and P Ͻ 0.05 was Chelles, France) warmed to 30°C to maintain stable cutaneous temperature. considered significant. Mice were placed in the prone position, and the head was fixed on a frame followed by a 20-min resting period to stabilize the blood pressure and the cutaneous temperature. Blood pressure was measured using a noninvasive RESULTS system (IITC, Woodland Hills, CA). The weighbridge was equilibrated care- Body weight and blood glucose and fructosamine fully with the probe placed in the middle of the hairless skull of the mouse, levels.
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