Short-term weight loss reverses obesity-induced microvascular endothelial dysfunction

Abstract

Obesity is one of the major risk factors for cardiovascular diseases and its prevalence is increasing in all age groups, with the biggest impact observed in middle-aged and older adults. A critical mechanism by which obesity promotes vascular pathologies in these patients involves impairment of endothelial function. While endothelial dysfunction in large vessels promotes atherogenesis, obesity-induced microvascular endothelial dysfunction impairs organ perfusion and thereby is causally related to the pathogenesis of ischemic heart disease, chronic kidney disease, intermittent claudication, exercise intolerance, and exacerbates cognitive decline in aging. Reduction of weight via calorie-based diet and exercise in animal models of obesity results in significant improvement of endothelial function both in large vessels and in the microcirculation, primarily due to attenuation of oxidative stress and inflammation. Clinical data on the protective effects of weight loss on endothelial function is limited to studies of flow-mediated dilation assessed in brachial arteries. Currently, there is no guideline on testing the effects of different weight management strategies on microvascular endothelial function in obese patients. Here, we provide proof-of-concept that weight loss-induced improvement of microvascular endothelial function can be reliably assessed in the setting of a geriatric outpatient clinic using a fast, reproducible, non-invasive method: laser speckle contrast imaging-based measurement of endothelium-dependent microvascular responses during post-occlusive reactive hyperemia tests. Our study also provides initial evidence that short-term weight loss induced by consumption of a low-carbohydrate low-calorie diet can reverse microvascular endothelial dysfunction associated with obesity.

Overexpression of catalase targeted to mitochondria improves neurovascular coupling responses in aged mice

“…Several lines of evidence support this view, including the observations that genetic deficiency of eNOS, pharmacological inhibition of NO synthesis, endothelial injury, and endotheliumspecific depletion of critical vasoprotective factors can similarly impair NVC responses (Tarantini et al 2018b(Tarantini et al , 2019Toth et al 2014Toth et al , 2015aChen et al 2014). Strong evidence demonstrates that aging associates with generalized endothelial dysfunction (Csiszar et al 2019;Csipo et al 2019;Ungvari et al 2018b). Extending previous findings in elderly patients and aged laboratory animals, we confirm that aging-induced impairment of cerebromicrovascular endothelial function critically contributes to neurovascular uncoupling in aged mammals (Tarantini et al 2017a(Tarantini et al , 2018b(Tarantini et al , 2019Park et al 2007).…”

“…NVC is responsible for increased oxygen and nutrient delivery to the activated neurons, for the effective wash-out of toxic metabolites and for maintenance of an optimal humoral microenvironment within the cerebral tissue. There is an increasing appreciation that vascular contributions to cognitive impairment and dementia (termed BVCID^) play a critical role in older individuals (Tarantini et al 2016;Carlson et al 2018;Csipo et al 2018;Gillon et al 2018;Ungvari et al 2018a;Csiszar et al 2017;Tarantini et al 2017b;Tucsek et al 2017;Ungvari et al 2017;Tarantini et al 2017cTarantini et al , 2018aTarantini et al , b, 2019Toth et al 2017). Importantly, NVC responses are impaired both in older adults (Lipecz et al 2019;Zaletel et al 2005;Topcuoglu et al 2009;Stefanova et al 2013;Fabiani et al 2013) and aged rodents (Tarantini et al 2018b(Tarantini et al , 2019Toth et al 2014;Park et al 2007), which contributes significantly to the progressive age-related decline in cognitive function (Sorond et al 2011(Sorond et al , 2013.…”

Age-dependent effects of caloric restriction on mTOR and ubiquitin-proteasome pathways in skeletal muscles

“…Generally speaking, reduced food intake by CR provides a wide spectrum of beneficial effects including reversion of obesity-related endothelial dysfunction (Csipo et al 2018), preservation of muscle mass of aging animals (Chen et al 2015), and prevention of many chronic diseases such as diabetes and cardiovascular diseases (Mattison et al 2017). Nevertheless, CR has potential adverse effects for certain biological systems and animals with specific genetic backgrounds (Contreras et al 2018) (Fang et al 2017).…”

Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment

“…4). Recent developments in our understanding of mechanisms of aging (Deepa et al 2017;Fang et al 2017;Grant et al 2017;Konopka et al 2017;Podlutsky et al 2017;Cunningham et al 2018;Habermehl et al 2018;Kim et al 2018;Lewis et al 2018;Masser et al 2018;Nacarelli et al 2018;Olecka et al 2018;Reglodi et al 2018) and vascular aging processes (Csiszar et al 2017;Tarantini et al 2017a, b;Tucsek et al 2017;Ungvari et al 2017a, b;Csipo et al 2018;Fulop et al 2018;Lee et al 2018;Reglodi et al 2018;Sure et al 2018;Ungvari et al 2018b, c) highlight the importance of in vitro screening assays that model complex physiological processes for the evaluation of the anti-aging effects of novel pharmacological interventions. The combination of the in vitro assays used in this study, based on rescue of age-related loss-of-function in endothelial cells, could correctly identify the anti-aging effects of caloric restriction (Csiszar et al 2013(Csiszar et al , 2014 as well as neuroendocrine factors (Banki et al 2015).…”