Pressure ulcers are common debilitating complications of diabetes that are caused by tissue ische... more Pressure ulcers are common debilitating complications of diabetes that are caused by tissue ischemia. Skin blood flow in response to locally applied pressure might be impaired in diabetic patients because of the combined effects of a typically low skin temperature and alterations in microcirculatory function, and could be worsened by neuropathy. We measured skin blood flow by laser Doppler flowmetry over the internal anklebone in response to local pressure applied at 5.0 mmHg/min in three groups of diabetic patients (with clinical and subclinical neuropathy and without neuropathy) and in healthy matched control subjects at usual room temperature. Compared with in matched control subjects with comparable skin temperatures (29.3 +/- 0.4 vs. 28.7 +/- 0.4 degrees C), in diabetic patients the skin blood flow response to locally applied pressure was further impeded, even in those without neuropathy. Indeed, skin blood flow decreased significantly from baseline at much lower applied pressure (7.5 mmHg) in diabetic subjects, again even in those without neuropathy, than in control subjects (48.8 mmHg). The large difference between these pressures could partially explain diabetic patients' high risk of developing decubitus and plantar ulcers.
Background—We sought to determine whether carbonic anhydrase (CA), which plays an important role ... more Background—We sought to determine whether carbonic anhydrase (CA), which plays an important role in bone resorption, contributes to vascular mineral loss induced by an endothelin receptor antagonist. Methods and Results—Wistar rats were compared with rats receiving warfarin and vitamin K1 (WVK) for 8 weeks alone or in association with the endothelin receptor antagonist darusentan (30 mg/kg per day), the CA
Advanced-glycation end products (AGEs) were recently implicated in vascular calcification, throug... more Advanced-glycation end products (AGEs) were recently implicated in vascular calcification, through a process mediated by RAGE (receptor for AGEs). Although a correlation between AGEs levels and vascular calcification was established, there is no evidence that reducing in vivo AGEs deposition or inhibiting AGEs-RAGE signaling pathways can decrease medial calcification. We evaluated the impact of inhibiting AGEs formation by pyridoxamine or elimination of AGEs by alagebrium on diabetic medial calcification. We also evaluated if the inhibition of AGEs-RAGE signaling pathways can prevent calcification. Rats were fed a high fat diet during 2 months before receiving a low dose of streptozotocin. Then, calcification was induced with warfarin. Pyridoxamine was administered at the beginning of warfarin treatment while alagebrium was administered 3 weeks after the beginning of warfarin treatment. Results demonstrate that AGEs inhibitors prevent the time-dependent accumulation of AGEs in femoral arteries of diabetic rats. This effect was accompanied by a reduced diabetes-accelerated calcification. Ex vivo experiments showed that N-methylpyridinium, an agonist of RAGE, induced calcification of diabetic femoral arteries, a process inhibited by antioxidants and different inhibitors of signaling pathways associated to RAGE activation. The physiological importance of oxidative stress was demonstrated by the reduction of femoral artery calcification in diabetic rats treated with apocynin, an inhibitor of reactive oxygen species production. We demonstrated that AGE inhibitors prevent or limit medial calcification. We also showed that diabetes-accelerated calcification is prevented by antioxidants. Thus, inhibiting the association of AGE-RAGE or the downstream signaling reduced medial calcification in diabetes.
In essential hypertension, conduit arteries present hypertrophic remodeling (increased cross-sect... more In essential hypertension, conduit arteries present hypertrophic remodeling (increased cross-sectional area), whereas small arteries undergo eutrophic remodeling. The involvement of matrix metalloproteinases (MMPs) and de-adhesion proteins, such as tenascin-C and thrombospondin, has been relatively well characterized in large artery remodeling, but their contribution is not known in small artery remodeling. Rats received N(omega)-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg per day) in their drinking water on days 1, 3, 7, 14, and 28. Arterial MMP-2 activity was measured by ELISA, whereas levels of tenascin-C and thrombospondin were assessed by Western blotting. To determine the involvement of MMPs, additional L-NAME rats received the nonselective MMP inhibitor doxycycline (30 mg/kg per day) on days 7, 14, and 28. Already, at day 1, pressure was elevated. Media/lumen ratio of mesenteric arteries and the aorta increased gradually to reach significance at 28 days. However, the cross-sectional area increased only in the aorta, confirming the heterogeneous remodeling process. In small arteries, MMP-2 activity increased after 7 and 14 days of treatment and returned to baseline at 28 days, whereas the elevation was more progressive but sustained in the aorta. The level of thrombospondin paralleled that of MMP-2 in small arteries, whereas tenascin-C levels declined rapidly and stayed below control values. Doxycycline blunted large artery remodeling but had no influence on the development of eutrophic remodeling despite elevation of MMP-2 activity in the process. Thus, in contrast to large artery hypertrophic remodeling, in which the contributions of cellular de-adhesion and matrix breakdown is manifest, the contribution of MMPs in eutrophic remodeling appears less crucial.
Pressure ulcers are common debilitating complications of diabetes that are caused by tissue ische... more Pressure ulcers are common debilitating complications of diabetes that are caused by tissue ischemia. Skin blood flow in response to locally applied pressure might be impaired in diabetic patients because of the combined effects of a typically low skin temperature and alterations in microcirculatory function, and could be worsened by neuropathy. We measured skin blood flow by laser Doppler flowmetry over the internal anklebone in response to local pressure applied at 5.0 mmHg/min in three groups of diabetic patients (with clinical and subclinical neuropathy and without neuropathy) and in healthy matched control subjects at usual room temperature. Compared with in matched control subjects with comparable skin temperatures (29.3 +/- 0.4 vs. 28.7 +/- 0.4 degrees C), in diabetic patients the skin blood flow response to locally applied pressure was further impeded, even in those without neuropathy. Indeed, skin blood flow decreased significantly from baseline at much lower applied pressure (7.5 mmHg) in diabetic subjects, again even in those without neuropathy, than in control subjects (48.8 mmHg). The large difference between these pressures could partially explain diabetic patients' high risk of developing decubitus and plantar ulcers.
Background—We sought to determine whether carbonic anhydrase (CA), which plays an important role ... more Background—We sought to determine whether carbonic anhydrase (CA), which plays an important role in bone resorption, contributes to vascular mineral loss induced by an endothelin receptor antagonist. Methods and Results—Wistar rats were compared with rats receiving warfarin and vitamin K1 (WVK) for 8 weeks alone or in association with the endothelin receptor antagonist darusentan (30 mg/kg per day), the CA
Advanced-glycation end products (AGEs) were recently implicated in vascular calcification, throug... more Advanced-glycation end products (AGEs) were recently implicated in vascular calcification, through a process mediated by RAGE (receptor for AGEs). Although a correlation between AGEs levels and vascular calcification was established, there is no evidence that reducing in vivo AGEs deposition or inhibiting AGEs-RAGE signaling pathways can decrease medial calcification. We evaluated the impact of inhibiting AGEs formation by pyridoxamine or elimination of AGEs by alagebrium on diabetic medial calcification. We also evaluated if the inhibition of AGEs-RAGE signaling pathways can prevent calcification. Rats were fed a high fat diet during 2 months before receiving a low dose of streptozotocin. Then, calcification was induced with warfarin. Pyridoxamine was administered at the beginning of warfarin treatment while alagebrium was administered 3 weeks after the beginning of warfarin treatment. Results demonstrate that AGEs inhibitors prevent the time-dependent accumulation of AGEs in femoral arteries of diabetic rats. This effect was accompanied by a reduced diabetes-accelerated calcification. Ex vivo experiments showed that N-methylpyridinium, an agonist of RAGE, induced calcification of diabetic femoral arteries, a process inhibited by antioxidants and different inhibitors of signaling pathways associated to RAGE activation. The physiological importance of oxidative stress was demonstrated by the reduction of femoral artery calcification in diabetic rats treated with apocynin, an inhibitor of reactive oxygen species production. We demonstrated that AGE inhibitors prevent or limit medial calcification. We also showed that diabetes-accelerated calcification is prevented by antioxidants. Thus, inhibiting the association of AGE-RAGE or the downstream signaling reduced medial calcification in diabetes.
In essential hypertension, conduit arteries present hypertrophic remodeling (increased cross-sect... more In essential hypertension, conduit arteries present hypertrophic remodeling (increased cross-sectional area), whereas small arteries undergo eutrophic remodeling. The involvement of matrix metalloproteinases (MMPs) and de-adhesion proteins, such as tenascin-C and thrombospondin, has been relatively well characterized in large artery remodeling, but their contribution is not known in small artery remodeling. Rats received N(omega)-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg per day) in their drinking water on days 1, 3, 7, 14, and 28. Arterial MMP-2 activity was measured by ELISA, whereas levels of tenascin-C and thrombospondin were assessed by Western blotting. To determine the involvement of MMPs, additional L-NAME rats received the nonselective MMP inhibitor doxycycline (30 mg/kg per day) on days 7, 14, and 28. Already, at day 1, pressure was elevated. Media/lumen ratio of mesenteric arteries and the aorta increased gradually to reach significance at 28 days. However, the cross-sectional area increased only in the aorta, confirming the heterogeneous remodeling process. In small arteries, MMP-2 activity increased after 7 and 14 days of treatment and returned to baseline at 28 days, whereas the elevation was more progressive but sustained in the aorta. The level of thrombospondin paralleled that of MMP-2 in small arteries, whereas tenascin-C levels declined rapidly and stayed below control values. Doxycycline blunted large artery remodeling but had no influence on the development of eutrophic remodeling despite elevation of MMP-2 activity in the process. Thus, in contrast to large artery hypertrophic remodeling, in which the contributions of cellular de-adhesion and matrix breakdown is manifest, the contribution of MMPs in eutrophic remodeling appears less crucial.
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Papers by Celine Bouvet