Anti-atherosclerotic Effects Of Angiotensin Fragments & Non-AT1 Receptors: Validation As Innovative Therapeutic Targets
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the horm ....In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the hormone, angiotensin II. Angiotensin II has been found to trigger many factors that cause thickening of the vessel wall, inflammation and imbalances in vasodilator capacity (e.g. oxidative stress and endothelial dysfunction), all of which contribute to atherosclerosis. Clinical trials with drugs that inhibit the formation of angiotensin II (ACE inhibitors), or block the action of angiotensin II (angiotensin receptor antagonists), have demonstrated a significant decrease in mortality in patients with high risk for cardiovascular disease. However their mechanism(s) of action are not fully understood as the circulating levels of shorter fragments of angiotensin II (such as Ang IV and Ang (1-7)) are raised in the blood when these drugs are used and may contribute to the protective effects of these drugs. Importantly, we have found that both Ang IV and Ang (1-7) have protective effects in atherosclerotic blood vessels. Therefore, we hypothesise that fragments of angiotensin II (such as Ang IV and others) exert anti-atherogenic effects via distinct binding sites that oppose the effects caused by angiotensin II, and that these may be partly responsible for the cardio-protective effects of the ACE inhibitors and angiotensin receptor antagonists. Thus, information gained in our study will be useful in directing future prescription practices in clinical management of CHD and stroke, and for designing new therapeutic compounds for the management of atherosclerosis.Read moreRead less
Our studies are aimed at examining how blood flow and pressure is controlled in the various tissues of the body. In particular, we hope to improve our understanding of how blood flow is matched to local metabolic requirements and how a constancy of conditions can be maintained despite changes in overall blood pressure. This ability to control local blood flow occurs through the ability of very small arteries to rapidly adjust their diameters through vasoconstriction or vasodilatation. The vessel ....Our studies are aimed at examining how blood flow and pressure is controlled in the various tissues of the body. In particular, we hope to improve our understanding of how blood flow is matched to local metabolic requirements and how a constancy of conditions can be maintained despite changes in overall blood pressure. This ability to control local blood flow occurs through the ability of very small arteries to rapidly adjust their diameters through vasoconstriction or vasodilatation. The vessels can thus act as valves regulating the transfer of blood flow and pressure to smaller vessels downstream. One particular response that small arteries exhibit is the ability to constrict when pressure within the vessels increases. The increase in pressure appears to stretch the vessel wall which in turn initiates a series of mechanical and biochemical steps that ultimately lead to contraction of muscle cells within the vessel wall. By contracting, the vessels limit the increase in downstream flow and pressure that would be expected to occur. The vessels being studied are very small, typically less than 100 micron. They are studied under isolated and controlled conditions using microscope and computer-based imaging techniques. While this allows us to directly monitor changes in vessel diameter to various stimuli (e.g. a change in pressure) we have also had to miniaturize biochemical measurements so we can understand the chemistry which underlies these vasoconstrictor responses. Understanding of how these local blood regulatory mechanisms occur is not only relevant to our understanding of the normal situation but is also vital to understanding disease states. For example, this work is very relevant to common cardiovascular disorders such as hypertension. It is hoped that a detailed understanding of the biochemical pathways by which small arteries contract will allow the design and targeting of pharmaceutical approaches for treatment of vascular disease states.Read moreRead less
Mechanisms Of Impaired Uterine Vascularisation In Early Pregnancy.
Funder
National Health and Medical Research Council
Funding Amount
$570,414.00
Summary
Vascular dysfunction and reduced blood flow to the placenta are underlying causes of pre-eclampsia and hypertension in pregnant women. Our proposal will identify if low circulating levels of the hormone relaxin are causes of abnormal development of the uterine vasculature in early pregnancy. This knowledge will enable us to develop new treatments to improve health outcomes in women at high risk of developing these diseases during their pregnancy.
MECHANISMS OF CEREBROVASCULAR REGULATION IN HEALTH AND DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$216,430.00
Summary
Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent and significant research at the basic level to better understand mechanisms of normal, and then abnormal, regulation of cerebral artery function. The project will examine the importance of a novel mechanism in regulating brain blood flow by affecting the ....Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent and significant research at the basic level to better understand mechanisms of normal, and then abnormal, regulation of cerebral artery function. The project will examine the importance of a novel mechanism in regulating brain blood flow by affecting the degree of opening of the cerebral arteries. This mechanism involves activation of an enzyme, Rho-kinase, which is present in the wall of blood vessels. The applicants believe that this process plays an important role in the normal, healthy regulation of blood supply to the brain. Moreover, there are strong reasons for us to speculate that the function of this enzyme is abnormally high in two disease states that are associated with an increased risk of stroke - high blood pressure and subarachnoid haemorrhage. We will employ a variety of techniques to assess the importance of Rho-kinase in cerebral artery function in the living body, and also in isolated segments of artery. The results are expected to provide major new insight into mechanisms that regulate brain blood flow, and the knowledge gained here may lead to better therapies to prevent or treat stroke.Read moreRead less
Peripheral Mechanisms Involved In Autonomic Hyperreflexia
Funder
National Health and Medical Research Council
Funding Amount
$229,917.00
Summary
Bladder distension or minor unheeded injuries below the lesion in spinally injured people often lead to episodes of high blood pressure that may cause stroke or death. These events require emergency hospitalization and are expensive as well as dangerous. After spinal injury, the control of sympathetic nerves that supply arteries and regulate blood pressure is lost. However, the nerves below the injury remain in place and the spinal cord below the lesion contains connections that can activate the ....Bladder distension or minor unheeded injuries below the lesion in spinally injured people often lead to episodes of high blood pressure that may cause stroke or death. These events require emergency hospitalization and are expensive as well as dangerous. After spinal injury, the control of sympathetic nerves that supply arteries and regulate blood pressure is lost. However, the nerves below the injury remain in place and the spinal cord below the lesion contains connections that can activate them. Signals from the bladder or skin enter the remaining lower part of the spinal cord and activate the sympathetic supply generating a rise in blood pressure. This project will test the hypothesis that increased sensitivity of arteries to the chemicals released from the sympathetic nerves leads to excessive vessel constriction, contributing to the exaggerated increase in pressure. We will investigate arteries removed from rats with experimental spinal transection. We will test the contractions of the arteries (a) to sympathetic nerve stimulation and (b) to the chemicals noradrenaline, adenosine 5'-triphosphate (ATP) and neuropeptide Y that are normally released during nerve activity. We will determine whether release of noradrenaline and ATP from nerves is normal or augmented using electrochemical and electrophysiological techniques. We will compare the responses with those in normal arteries, those in arteries whose nerves have been silenced by removing all connections from the spinal cord and those in arteries that have lost all their nerve supply. This will enable us to identify whether the mechanisms for release of transmitter substances are modified and whether the arterial muscle is hypersensitive to these substances. The results will help in the design of safer treatment for these potentially lethal emergencies in spinal patients.Read moreRead less
Study Of The Functional Consequences Of Angiotensin II Induced Increases In Renal Innervation
Funder
National Health and Medical Research Council
Funding Amount
$393,750.00
Summary
Hypertension (high blood pressure) is a major public health problem in Australia, being a key risk factor for cardiovascular diseases such as heart attack and stroke. More ominously, recent WHO reports show that cardiovascular disease is the major health burden facing developing countries, particularly in our region. Although some of the burden of cardiovascular diseases may be reduced by effective public health measures (e.g., to reduce saturated fat intake), hypertension remains largely imperv ....Hypertension (high blood pressure) is a major public health problem in Australia, being a key risk factor for cardiovascular diseases such as heart attack and stroke. More ominously, recent WHO reports show that cardiovascular disease is the major health burden facing developing countries, particularly in our region. Although some of the burden of cardiovascular diseases may be reduced by effective public health measures (e.g., to reduce saturated fat intake), hypertension remains largely impervious to preventative public health measures. While treatment of established high blood pressure can reduce the incidence of cardiovascular disease, preventing the development of hypertension in the first place is not possible at this time. A major impediment to the development of effective public health measure is our lack of knowledge of the pathological mechanisms involved, despite over 100 years of active research effort. The experiments planned in this study will probe below the surface of two important facts known about hypertension but not previously brought together - that the kidney's blood vessels and nerves are remodeled in hypertension, and that the kidney's control of the level of blood pressure must be changed in order for high blood pressure to develop in the first place. We hope that pursuit of this experimental line of enquiry will provide new clues on where to look for initiating factors in human hypertension.Read moreRead less
The Role Of Connexins In Blood Pressure Regulation: Use Of A Conditional Gene Expression System
Funder
National Health and Medical Research Council
Funding Amount
$583,767.00
Summary
Cell coupling through gap junctions is said to play an important role in regulating blood flow and blood pressure. However data obtained from mice, in which specific gap junctions are deleted, may be compromised by compensatory changes in other junctions. We have validated a new method for rapidly and reversibly altering gap junctions in adult mice with oral sugar. This technique will enable us to directly determine whether interference with cell coupling affects blood flow and blood pressure.
Cerebrovascular Effects Of Intrauterine Hypoxia: Contribution To Perinatal Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$579,138.00
Summary
During pregnancy, delivery of oxygen and nutrients to the growing fetus is sometimes disturbed, and can lead to injury of the developing brain. In this project we investigate the idea that low oxygen (hypoxia) causes brain demage to blood vessels in the fetal brain, and new blood vessesl produced in an attempt to repair this damage are fragile and prone to rupture, explaining the high incidence of bleeding in the brain of prematurely-born and full term infants that experience birth hypoxia.
Mechanisms Underlying Disordered Skin Blood Flow Following Nerve Injury
Funder
National Health and Medical Research Council
Funding Amount
$408,000.00
Summary
Many people who recover from traumatic injury or who have chronic conditions such as diabetes or neuropathy from exposure to a toxic chemical suffer from peripheral vascular disorders leading to poor circulation in the extremities. These conditions are characterised by impaired wound healing, cold hands and feet and ongoing pain. These people must face a long life with progressively increasing disability. Even normal ageing can lead to similar problems. This project is directed at understanding ....Many people who recover from traumatic injury or who have chronic conditions such as diabetes or neuropathy from exposure to a toxic chemical suffer from peripheral vascular disorders leading to poor circulation in the extremities. These conditions are characterised by impaired wound healing, cold hands and feet and ongoing pain. These people must face a long life with progressively increasing disability. Even normal ageing can lead to similar problems. This project is directed at understanding the role of the nerve supply to blood vessels in the skin in these disorders. The experiments will be conducted in skin blood vessels of rats with various forms of nerve lesion that will mimic these conditions in patients. We will use our knowledge of the structure and behaviour of nerve-blood vessel connections to analyse the changes in the properties of vascular smooth muscle and relate it to the state of the innervation. Skin arteries normally receive two types of nerve - sympathetic (which release noradrenaline) and afferent ( which release peptides) - that have opposing actions on the vessel (constriction and dilation respectively). We hypothesize that removal of part or all of the innervation changes the contractile mechanism of the smooth muscle in the wall of the vessel so that it becomes much more sensitive to calcium ions and produces larger and more prolonged contractions. We will combine electrophysiology and contraction studies with immunohistochemistry and biochemical analysis to define the relation between the nerve deficit and the vascular responses. The aim is to identify appropriate drug targets for which local application in the affected region can alleviate the symptoms without causing widespread side effects.Read moreRead less