The role of vascular endothelial growth factor in heart failure with preserved ejection fraction

To this day heart failure with preserved ejection fraction (HFpEF) remains a poorly understood malady. Half of all heart failure (HF) cases are HFpEF, and the prevalence of HF is on the rise. Unlike HF with reduced ejection fraction, HFpEF has no treatment options and is often times difficult to dia...

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Main Author: Glazyrine, Vassili
Language:en_US
Published: 2016
Subjects:
Online Access:https://hdl.handle.net/2144/16220
id ndltd-bu.edu-oai-open.bu.edu-2144-16220
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spelling ndltd-bu.edu-oai-open.bu.edu-2144-162202019-03-17T03:21:02Z The role of vascular endothelial growth factor in heart failure with preserved ejection fraction Glazyrine, Vassili Medicine HFpEF Adult rat ventricular myocyte Heart failure Preserved ejection fraction Vascular endothelial growth factor Vascular smooth muscle cells To this day heart failure with preserved ejection fraction (HFpEF) remains a poorly understood malady. Half of all heart failure (HF) cases are HFpEF, and the prevalence of HF is on the rise. Unlike HF with reduced ejection fraction, HFpEF has no treatment options and is often times difficult to diagnose because victims of HFpEF often have pre-existing conditions. Vascular endothelial growth factor (VEGF) has been implicated in maintaining myocardial health and is thought to play a role in HFpEF. We sought to test the hypothesis that VEGF-A plays a role in HFpEF in a hypertensive murine model of HFpEF. Using Western blot analysis we found that there was an up regulation of VEGF-A in the homogenized left ventricle (LV) of our HFpEF mice. Unexpectedly, there was a down regulation of VEGF-A in the homogenized tissue from the aorta in those mice. To study the circulating levels of VEGF in our HFpEF mice we used an ELISA. We found that our HFpEF mice had similar levels of circulating VEGF as our control. This suggests that VEGF has paracrine/autocrine role in our HFpEF model rather than endocrine, like our human data suggested. To identify the cells responsible for the expression profile we saw in the homogenized tissue data we looked at the response of adult rat ventricular myocytes (ARVM) and vascular smooth muscle cells (VSMC) to aldosterone stimulation at short (1hr) and long (24hr) time points at both physiological (50nm) and pathological (1μm) concentrations. To do this analysis we recruited the help of Western blot, ELISA and RT-PCR techniques to construct a consistent VEGF expression profile. The Western blot ARVM data showed statistically significant (P<0.05) increase in VEGF-A to pathological doses of aldosterone, especially at the longer time point. When we tested the VSMC using Western blot analysis, we found that the trend of our n=1 sample suggested a strong response to the physiological dose of aldosterone in the short term. Using the more sensitive ELISA technique to measure the VEGF content of our VCMS we increasing our sample size to n=4 and found no statistically significant (p=NS) response to aldosterone stimulation from the VSMC. However, looking at the trends in the data it is clear that VSMC increases VEGF in response to long-term physiological doses of aldosterone. This is contrary to what we found using Western blot analysis, so we queried the VEGF mRNA from the VSMC to settle the score. Unfortunately, this too proved fruitless. The RT-PCR data was not significant and the trend was that of the ARVM expression profile. We initially turned to VSMC because we hypothesized that they could contribute to the paracrine/autocrine activity similar to what we saw in the LV from the ARVM. It is unclear if VSMC play a role in HFpEF progression, but their lack of consistent response to aldosterone could potential explain the down regulation of VEGF-A we observed in the aorta of our HFpEF mice. We initially sough to test the hypothesis that VEGF-A plays a role in our HFpEF mouse model, what we found was that ARVM contribute to localized VEGF-A increased production in the LV while in the aorta there is a down regulation of VEGF-A in our HFpEF model, we are unable to make any conclusion about VSMC response to aldosterone because of insufficient sample size. Thus in conclusion, it appears that VEGF-A does play a role in our HFpEF model specifically in a paracrine/autocrine manner in the LV where the ARVM contributes to the increased production of the cytokine. 2016-05-06T15:31:03Z 2016-05-06T15:31:03Z 2015 2016-04-08T20:18:47Z Thesis/Dissertation https://hdl.handle.net/2144/16220 en_US
collection NDLTD
language en_US
sources NDLTD
topic Medicine
HFpEF
Adult rat ventricular myocyte
Heart failure
Preserved ejection fraction
Vascular endothelial growth factor
Vascular smooth muscle cells
spellingShingle Medicine
HFpEF
Adult rat ventricular myocyte
Heart failure
Preserved ejection fraction
Vascular endothelial growth factor
Vascular smooth muscle cells
Glazyrine, Vassili
The role of vascular endothelial growth factor in heart failure with preserved ejection fraction
description To this day heart failure with preserved ejection fraction (HFpEF) remains a poorly understood malady. Half of all heart failure (HF) cases are HFpEF, and the prevalence of HF is on the rise. Unlike HF with reduced ejection fraction, HFpEF has no treatment options and is often times difficult to diagnose because victims of HFpEF often have pre-existing conditions. Vascular endothelial growth factor (VEGF) has been implicated in maintaining myocardial health and is thought to play a role in HFpEF. We sought to test the hypothesis that VEGF-A plays a role in HFpEF in a hypertensive murine model of HFpEF. Using Western blot analysis we found that there was an up regulation of VEGF-A in the homogenized left ventricle (LV) of our HFpEF mice. Unexpectedly, there was a down regulation of VEGF-A in the homogenized tissue from the aorta in those mice. To study the circulating levels of VEGF in our HFpEF mice we used an ELISA. We found that our HFpEF mice had similar levels of circulating VEGF as our control. This suggests that VEGF has paracrine/autocrine role in our HFpEF model rather than endocrine, like our human data suggested. To identify the cells responsible for the expression profile we saw in the homogenized tissue data we looked at the response of adult rat ventricular myocytes (ARVM) and vascular smooth muscle cells (VSMC) to aldosterone stimulation at short (1hr) and long (24hr) time points at both physiological (50nm) and pathological (1μm) concentrations. To do this analysis we recruited the help of Western blot, ELISA and RT-PCR techniques to construct a consistent VEGF expression profile. The Western blot ARVM data showed statistically significant (P<0.05) increase in VEGF-A to pathological doses of aldosterone, especially at the longer time point. When we tested the VSMC using Western blot analysis, we found that the trend of our n=1 sample suggested a strong response to the physiological dose of aldosterone in the short term. Using the more sensitive ELISA technique to measure the VEGF content of our VCMS we increasing our sample size to n=4 and found no statistically significant (p=NS) response to aldosterone stimulation from the VSMC. However, looking at the trends in the data it is clear that VSMC increases VEGF in response to long-term physiological doses of aldosterone. This is contrary to what we found using Western blot analysis, so we queried the VEGF mRNA from the VSMC to settle the score. Unfortunately, this too proved fruitless. The RT-PCR data was not significant and the trend was that of the ARVM expression profile. We initially turned to VSMC because we hypothesized that they could contribute to the paracrine/autocrine activity similar to what we saw in the LV from the ARVM. It is unclear if VSMC play a role in HFpEF progression, but their lack of consistent response to aldosterone could potential explain the down regulation of VEGF-A we observed in the aorta of our HFpEF mice. We initially sough to test the hypothesis that VEGF-A plays a role in our HFpEF mouse model, what we found was that ARVM contribute to localized VEGF-A increased production in the LV while in the aorta there is a down regulation of VEGF-A in our HFpEF model, we are unable to make any conclusion about VSMC response to aldosterone because of insufficient sample size. Thus in conclusion, it appears that VEGF-A does play a role in our HFpEF model specifically in a paracrine/autocrine manner in the LV where the ARVM contributes to the increased production of the cytokine.
author Glazyrine, Vassili
author_facet Glazyrine, Vassili
author_sort Glazyrine, Vassili
title The role of vascular endothelial growth factor in heart failure with preserved ejection fraction
title_short The role of vascular endothelial growth factor in heart failure with preserved ejection fraction
title_full The role of vascular endothelial growth factor in heart failure with preserved ejection fraction
title_fullStr The role of vascular endothelial growth factor in heart failure with preserved ejection fraction
title_full_unstemmed The role of vascular endothelial growth factor in heart failure with preserved ejection fraction
title_sort role of vascular endothelial growth factor in heart failure with preserved ejection fraction
publishDate 2016
url https://hdl.handle.net/2144/16220
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