8 research outputs found
Effect of chronic endothelin receptor antagonism on cerebrovascular function in type 2 diabetes
Differential Effects of Diet-Induced Dyslipidemia and Hyperglycemia on Mesenteric Resistance Artery Structure and Function in Type 2 Diabetes
Type 2 diabetes and dyslipidemia oftentimes present in combination.
However, the relative roles of diabetes and diet-induced dyslipidemia in
mediating changes in vascular structure, mechanics, and function are poorly
understood. Our hypothesis was that addition of a high-fat diet would
exacerbate small artery remodeling, compliance, and vascular dysfunction in
type 2 diabetes. Vascular remodeling indices [media/lumen (M/L) ratio,
collagen abundance and turnover, and matrix metalloproteinase dynamics],
mechanical properties (vessel stiffness), and reactivity to pressure and
vasoactive factors were measured in third-order mesenteric arteries in control
Wistar and type 2 diabetic Goto-Kakizaki (GK) rats fed either a regular or
high-fat diet. M/L ratios, total collagen, and myogenic tone were increased in
diabetes. Addition of the high-fat diet altered collagen patterns (mature
versus new collagen) in favor of matrix accumulation. Addition of a high-fat
diet caused increased constriction to endothelin-1 (0.1–100 nM), showed
impaired vasorelaxation to both acetylcholine (0.1 nM–1 μM) and
sodium nitroprusside (0.1 nM–1 μM), and increased cardiovascular risk
factors in diabetes. These results suggest that moderate elevations in blood
glucose, as seen in our lean GK model of type 2 diabetes, promote resistance
artery remodeling resulting in increased medial thickness, whereas addition of
a high-fat diet contributes to diabetic vascular disease predominantly by
impairing vascular reactivity in the time frame used for this study. Although
differential in their vascular effects, both hyperglycemia and diet-induced
dyslipidemia need to be targeted for effective prevention and treatment of
diabetic vascular disease
Glycemic control prevents microvascular remodeling and increased tone in Type 2 diabetes: link to endothelin-1
Medial thickening and vascular hypertrophy of resistance arteries can lead to cardiovascular complications associated with diabetes. While previous studies have established a role of Type 1 diabetes in vascular remodeling, we recently extended these observations to Type 2 diabetes and reported increased collagen deposition due to alterations in matrix metalloproteinase expression and activity in mesenteric resistance arteries. These studies also showed that remodeling response was mediated by endothelin-1 (ET-1) via activation of ETA receptors, whereas blockade of ETB receptors exacerbated the remodeling. However, the effectiveness of glycemic control strategies in preventing these vascular changes, including activation of the ET system still remained unclear. Also, very little is known about whether and to what extent reorganization of the extracellular matrix (ECM) affects vascular compliance and vasomotor tone. Accordingly, this study assessed structural remodeling of mesenteric microvessels, vascular compliance, and myogenic tone, as well as the role of matrix metalloproteinases (MMP) in mediating these processes. Spontaneously diabetic, non-obese Goto-Kakizaki (GK) rats, a model for Type 2 diabetes, and normoglycemic Wistar rats were used for the studies. A subset of GK rats were administered metformin to achieve euglycemia. Glycemic control normalized the increased media-to-lumen ratios (M/L) and myogenic tone seen in diabetes, as well as normalizing plasma ET-1 levels and mesenteric ETA receptor expression. There was increased collagen synthesis in diabetes paralleled by decreased collagenase MMP-13 activity, while glycemic control attenuated the process. These findings and our previous study taken together suggest that hyperglycemia-mediated activation of ET-1 and ETA receptors alter vascular structure and mechanics in Type 2 diabetes
Effect of chronic and selective endothelin receptor antagonism on microvascular function in Type 2 diabetes
Formation of endothelial lumens requires a coordinated PKCε-, Src-, Pak- and Raf-kinase-dependent signaling cascade downstream of Cdc42 activation
In this study, we present data showing that Cdc42-dependent lumen formation
by endothelial cells (ECs) in three-dimensional (3D) collagen matrices
involves coordinated signaling by PKCε in conjunction with the Src-family
kinases (SFKs) Src and Yes. Activated SFKs interact with Cdc42 in multiprotein
signaling complexes that require PKCε during this process. Src and Yes
are differentially expressed during EC lumen formation and siRNA suppression
of either kinase, but not Fyn or Lyn, results in significant inhibition of EC
lumen formation. Concurrent with Cdc42 activation, PKCε- and
SFK-dependent signaling converge to activate p21-activated kinase (Pak)2 and
Pak4 in steps that are also required for EC lumen formation. Pak2 and Pak4
further activate two Raf kinases, B-Raf and C-Raf, leading to ERK1 and ERK2
(ERK1/2) activation, which all seem to be necessary for EC lumen formation.
This work reveals a multicomponent kinase signaling pathway downstream of
integrin-matrix interactions and Cdc42 activation involving PKCε, Src,
Yes, Pak2, Pak4, B-Raf, C-Raf and ERK1/2 to control EC lumen formation in 3D
collagen matrices