2016 — 2019 |
Wang, Dan Wilcox, Christopher S |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Accelerated Aging of Microvessels and Perivascular Adipose Tissue in Women With Hiv
SUMMARY Antiretroviral therapy (ART) has increased the life expectancy of human subjects infected with the human immunodeficiency virus (HIV), but many now suffer from an increased frequency and earlier onset of vascular events whose mechanisms are not yet clear. We reported reduced endothelium derived relaxation factor (EDRF) and nitric oxide (NO) in isolated living subdermal microvessels from otherwise risk-free young women with well- controlled HIV. The perivascular adipose tissue (PVAT) surrounding blood vessels normally enhances EDRF/NO. However, HIV and ART both can induce lipoatrophy and adipose inflammation and might thereby impair the augmented EDRF/NO response from PVAT. We found that incubation of vascular cells with HIV Tat protein or tenofovir (component of ART) increased cellular senescence signaling and microRNA-34a. How dysfunction of the endothelium, PVAT and miRNAs contribute to premature microvascular aging is unknown, but our results suggest it may entail increased reactive oxygen species (ROS) which we have detected in the blood vessels and PVAT of HIV positive subjects. We will test the hypothesis that HIV infection and/or ART generate ROS to transcribe specific miRNAs that engage the cellular senescence pathway in microvascular endothelium and PVAT. This impairs endothelial function and NO generation and limits their augmentation by adiponectin and other adipokines release from PVAT. We propose to recruit five groups of women from the Washington DC Women's Interagency HIV Study (WIHS) program or Georgetown University Hospital HIV Clinic: HIV negative, young (21-45 years, group 1) and old (50-80 years, group 2) controls and HIV positive women receiving ART, young (21-45 years, group 3) and old (50-80 years, group 4), or young HIV negative women who are receiving pre-exposure prophylaxis (PrEP, group 5; Aim 2 only). Aim 1 (ex vivo, group 1-4) will evaluate the specific pathways and molecules that mediate accelerated age-dependent endothelial dysfunction in the microvessels and PVAT of HIV positive women and will seek the mediators and adipokines responsible. Aim 2 (in vivo, group 1-5) will use non-invasive iontophoretic application of acetylchonline and measurements of cutaneous blood flow using Laser Doppler Flowmetry ( LDF). It will assess endothelial function in dermal blood vessels to evaluate the separate effects of aging, HIV and ART (using HIV negative women receiving ART for PrEP). The two aims will incorporate a novel concept from preliminary cellular and clinical studies that specific microRNAs provide a biological clock of cellular senescence with which to calibrate rapid microvascular aging in HIV. This will be the first study to explore premature aging in microvessels and its external regulation by PVAT and microRNAs in HIV positive individuals and may identify candidate targets for subsequent clinical trials intervention.
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0.948 |
2020 — 2021 |
Scott, Rachel K Wang, Dan |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Placental Microvasculature in Pregcies Complicated by Hiv
PROJECT SUMMARY Disparate outcomes in HIV positive pregnancies, such as fetal growth restriction (FGR), are etiologically poorly understood, but are attributed to uteroplacental insufficiency. FGR is a serious adverse outcome with associated lasting morbidity for the HIV exposed infant. Further research is desperately needed to better understand the placental pathophysiology in order to predict, diagnose, monitor, and potentially prevent FGR. Our previous research demonstrated increased microvascular oxidative stress in reproductive age women living with HIV (WLHIV) and alludes to a possible placental pathophysiology. Gluteal biopsies in premenopausal WLHIV without overt cardiovascular risk factors revealed severe endothelial dysfunction and reduced nitric oxide. These finding in non-pregnant WLHIV may represent early markers of future cardiovascular morbidity and beg the question of possible systemic microvascular dysfunction, including in the placenta. Although these findings in gluteal tissue cannot be directly extrapolated to placental microvasculature, we hypothesize that there is of potential systemic effect of HIV infection or ART on microvascular pathophysiology, similarly affecting the placenta, with a detrimental effect on fetal growth. The limited literature on human placental microvessels, particularly studies of placentas with growth restriction, yielded conflicting results largely attributable to methodological inconsistencies. To further explore this hypothesis, we are proposing a pilot study to replicate the methodology used in gluteal tissue in placental tissue and to characterize differences in placental microvascular nitric oxide (NO), reactive oxygen species (ROS), contractility, and endothelial dysfunction in pregnancies complicated by HIV and growth restriction. Addressing HIV-associated comorbidities and complications, specifically cardiovascular, are stated priorities of the NIH Office of AIDS Research and better understanding the underlying pathophysiology of the adverse outcomes related to pregnancies complicated by HIV have critically important implications for WLHIV and their pregnancies. Specifically our aims are 1) To determine the best methods of measuring contractility and endothelial function of microvessels in the human placenta and to adapt laboratory methodologies previously employed to measure the same parameters in gluteal tissue; 2) To undertake a quantitative evaluation of differences in microvascular NO, ROS, contractility, and endothelial dysfunction in 12 placentas of pregnancies complicated by HIV with and without FGR and 12 placentas of pregnancies in HIV-negative matched controls with and without FGR. This pilot research is the crucial next step to better understanding, diagnosing and managing the placental pathophysiology associated with adverse fetal and neonatal outcomes in pregnancies complicated by HIV.
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0.948 |