Endothelial PPARγ (Peroxisome Proliferator–Activated Receptor-γ) Is Essential for Preventing Endothelial Dysfunction With Aging

Abstract

Little is known about mechanisms that control vascular aging, particularly at the cell-specific level. PPARγ (peroxisome proliferator-activated receptor-γ) exerts protective effects in the vasculature when activated pharmacologically. To gain insight into the cell-specific impact of PPARγ, we examined the hypothesis that genetic interference with endothelial PPARγ would augment age-induced vascular dysfunction. We studied carotid arteries from adult (11.6±0.3 months) and old (24.7±0.6 months) mice with endothelial-specific expression of a human dominant negative mutation in PPARγ driven by the vascular cadherin promoter (E-V290M), along with age-matched, nontransgenic littermates. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation in arteries from adult nontransgenic and E-V290M mice and old nontransgenic mice. In contrast, responses to acetylcholine were reduced by >50% in old male and female E-V290M mice (<0.01). Endothelial function in old E-V290M mice was not altered by an inhibitor of COX (cyclooxygenase) but was restored to normal by a superoxide scavenger, an inhibitor of NADPH oxidase, or inhibition of ROCK (Rho kinase). Relaxation of arteries to nitroprusside, which acts directly on vascular muscle, was similar in all groups. Vascular expression of IL (interleukin)-6, Nox-2, and CDKN2A (a marker of senescence) was significantly increased in old E-V290M mice compared with controls (<0.05). These findings provide the first evidence that age-related vascular dysfunction, inflammation, and senescence is accelerated after interference with endothelial PPARγ via mechanisms involving oxidative stress and ROCK. The finding of an essential protective role for endothelial PPARγ has implications for vascular disease and therapy for vascular aging.

Endothelial Dysfunction in Diabetic Retinopathy

“…Its disruption leads to disorders of fatty acid/lipid metabolism, insulin resistance, and vascular pathology. Endothelial PPARγ is essential for preventing endothelial dysfunction with aging (42,43). Impaired endothelial PPARγ causes age-related vascular dysfunction.…”

Endothelial PPARγ (Peroxisome Proliferator–Activated Receptor-γ) Protects From Angiotensin II–Induced Endothelial Dysfunction in Adult Offspring Born From Pregnancies Complicated by Hypertension

“…A subpressor dose of Ang-II (120 ng/kg/min) was employed because we previously showed that E-V290M exhibit increased susceptibility and sensitivity to stressors including high fat diet, Ang-II and aging. 23,25,27 Administration of a sub-pressor dose of Ang-II did not affect SBP irrespective of genotype or pregnancy in either male or female offspring (Figure 2A). Endothelium-dependent relaxation was not affected in Ang-II-treated male nor female NT offspring born from AVP-infused pregnancies (Figure 2B).…”

“…Adult male and female transgenic mice expressing a dominant-negative mutation in human PPARγ under the control of an endothelial-specific vascular cadherin promoter (E-V290M) were used as experimental models as described below. 23,[25][26][27] Animals were maintained in conventional housing on a standard 12-hour light cycle with ambient temperature of 25°C. Mice were fed standard chow and were allowed drinking water ad libitum.…”

“…E-V290M mice exhibit impaired vasodilation in response to cardiovascular stressors such as high fat diet, renin-angiotensin system activation and aging. [23][24][25] In light of this increased sensitivity to endothelial impairment, we tested the hypothesis that loss of endothelial PPARγ activity in pups born from a pregnancy complicated by hypertension enhances the risk for cardiovascular dysfunction compared to their non-transgenic (NT) littermates. Herein, we provide evidence that genetic interference with PPARγ in the endothelium predisposes adult male and female offspring born from AVP-infused pregnancies to endothelial dysfunction.…”

Endothelial Aldehyde Dehydrogenase 2 as a Target to Maintain Vascular Wellness and Function in Ageing

“…As introduced above, a large number of risk factors plays a role in the development of CVDs, especially ageing which is associated with well-characterized phenotypes [8,13,14]. Over time, aged blood vessels become stiffer and thicker, and their ability to release vasoactive mediators, particularly NO, decreases, while vascular permeability increases, associated with the process of mild vessel inflammation, increased vessel thickness and compromised angiogenic response [14][15][16][17][18]. Of note, even if age remains the main determinant of vascular senescence, healthy vascular ageing can be achieved, and endothelial function is a key element of the heathy vasculature.…”