Interference With PPARγ Signaling Causes Cerebral Vascular Dysfunction, Hypertrophy, and Remodeling

Abstract

Abstract-The transcription factor PPAR␥ is expressed in endothelium and vascular muscle where it may exert antiinflammatory and antioxidant effects. We tested the hypothesis that PPAR␥ plays a protective role in the vasculature by examining vascular structure and function in heterozygous knockin mice expressing the P465L dominant negative mutation in PPAR␥ (L/ϩ). In L/ϩ aorta, responses to the endothelium-dependent agonist acetylcholine (ACh) were not affected, but there was an increase in contraction to serotonin, PGF 2␣ , and endothelin-1. In cerebral blood vessels both in vitro and in vivo, ACh produced dilation that was markedly impaired in L/ϩ mice. Superoxide levels were elevated in cerebral arterioles from L/ϩ mice and responses to ACh were restored to normal with a scavenger of superoxide. Diameter of maximally dilated cerebral arterioles was less, whereas wall thickness and cross-sectional area was greater in L/ϩ mice, indicating cerebral arterioles underwent hypertrophy and remodeling. Thus, interference with PPAR␥ signaling produces endothelial dysfunction via a mechanism involving oxidative stress and causes vascular hypertrophy and inward remodeling. These findings indicate that PPAR␥ has vascular effects which are particularly profound in the cerebral circulation and provide genetic evidence that PPAR␥ plays a critical role in protecting blood vessels. (Hypertension. 2008;51:867-871.)Key Words: endothelial function Ⅲ dominant negative Ⅲ hypertension Ⅲ remodeling Ⅲ hypertrophy T he peroxisome proliferator-activated receptor gamma (PPAR␥) is a ligand-activated transcription factor which has gained prominence because of its involvement in complex diseases such as diabetes, obesity, atherosclerosis, and hypertension. Recent interest in the role of PPAR␥ in the vasculature has substantially increased because of the antiinflammatory and antioxidant effects reported for PPAR␥ agonists (reviewed by Schiffrin et al 1 ). Naturally occurring mutations in humans, resulting in either constitutive activation or impairment of PPAR␥ function, strongly support its physiological importance and illustrate the severe consequences for cardiovascular related events when PPAR␥ signaling is altered. 2 Individuals with dominant negative mutations in PPAR␥ present with early onset hypertension and elements of the metabolic syndrome. 2 Although the importance of PPAR␥ in adipose tissue is now well documented, its role in the cardiovascular system has only begun to emerge. PPAR␥ is the molecular target of the thiazolidinediones (TZDs) class of antidiabetes drugs. These drugs increase insulin sensitivity but also lower blood pressure in patients with type 2 diabetes 3 and in animal models of hypertension. 4 TZDs also improve endothelial function and reduce blood pressure in nondiabetic models of hypertension, underscoring the potential protective effects of PPAR␥ in the vessel wall. 5 PPAR␥ is expressed in endothelium and vascular muscle and there is growing evidence that PPAR␥ may have direct effects in the vasculature. 6 ...

Chronic renal failure alters endothelial function in cerebral circulation in mice

“…PPAR␥ plays a critical role in protecting blood vessels (33), and interference with PPAR␥ signaling produces cerebral arteriolar endothelial dysfunction via a mechanism involving oxidative stress. The end result is cerebral vascular hypertrophy and inward remodeling (7). Thus the decrease in endothelial function in cerebral arterioles may result from a decrease in vasoprotective mechanisms rather than an increase in oxidative stress or inflammatory status.…”

HO-1 Induced by Cilostazol Protects Against TNF-α-associated Cytotoxicity via a PPAR-γ-dependent Pathway in Human Endothelial Cells

“…Although the mechanism by which HO-1 inhibits endothelial injury via cilostazol is not fully understood, some studies suggested that PPAR activity might have anti-inflammatory and vasculoprotective benefits [23,[30][31][32]. Thus, it was hypothesized that the cytoprotective effect of HO-1 against inflammatory cytokine-induced endothelial injury is dependent on PPAR activity.…”

Chronic Production of Peroxynitrite in the Vascular Wall Impairs Vasorelaxation Function in SHR/NDmcr-cp Rats, an Animal Model of Metabolic Syndrome

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