Role of defective Kv7.4 channels in vascular disease.

Context: Having high blood pressure increases the chances of heart attacks, strokes or kidney damage and the poor health that is associated with these diseases. Persistently narrowed blood vessels limits the flow of blood to important organs like the kidney, heart or brain and at the same time puts a strain on the heart. Potassium channels produced by the KCNQ family of genes are proteins that provide a pathway to allow potassium ions out of the cell and in doing so reduce the likelihood of muscle cells in the wall of blood vessels from contracting. This in turn improves the ease at which blood flows through blood vessels. Recently the applicant's group showed that these channels contribute to physiological dilators of blood vessels such as adrenaline but they become less effective in high blood pressure.

Aims:The proposed work will study proteins encoded by KCNQ genes in the arteries serving the kidney and brain in rats that have normal blood pressure and ones with high blood pressure. It will also do the same comparison in abdominal arteries from patients undergoing routine surgery who have normal or high blood pressure. The project will identify how these specific protein pores are opened by chemicals found in our blood to keep blood vessels open and to understand how they may become less effective in disease.

Benefits: Understanding how a blood vessel can be kept open is crucial for developing new treatments for when these processes go wrong. The proposed body of work will provide fundamental information on how KCNQ proteins stop blood vessels from becoming overly constricted and the factors that cause these proteins to have less functional impact in disease conditions. As such it will provide new lines of therapeutic treatment as well as enhancing our basic understanding of blood vessel control and disease mechanisms .

Opening of voltage-dependent potassium channels encoded by the KCNQ4 gene (Kv7.4) maintain vascular smooth muscle in a relaxed state and also underlie vasodilations by physiological mediators. However, dysfunction of Kv7.4 is a major feature of arteries from hypertensive animals. More importantly, as Kv7.4 has a key role in renal arteries then defective Kv7 channels may be central to the development of high blood pressure. The intended project will build upon the foundation studies by the applicant and will determine by quantitative PCR and western blot analysis how the expression of KCNQ genes alters in the renal and cerebral arteries as rats develop hypertension. KCNE1-5 gene products alter the biophysical properties of Kv7.4 so this project will use a molecular interference approach to assess the role of KCNE-products in vascular tone and will determine how the expression of these genes is affected by hypertension. These studies will be consolidated by isometric tension recording and patch clamp electrophysiology on isolated smooth muscle cells and HEK293 cells heterologously expressing KCNQ4, which will define how the Kv7.4 channel is stimulated by beta-adrenoceptor agonists. The factors dictating the membrane abundance of Kv7.4 and the impact of angiotensin II on protein levels will be elucidated by Western blot analysis and immunocytochemistry.

The goal of the research is that through a better understanding of how Kv7 channels govern vascular tone novel therapeutics for vascular disease can be developed. These findings can also be applied to other non-vascular smooth muscle (eg uterus) where Kv7 channels have been shown to have a functional role. There are a number of beneficiaries to this research beyond researchers in the immediate and allied fields.


1. Phd students and undergraduates at St George's as well as research staff from collaborators labs will benefit from the findings of the proposed research and the energetic environment it generates. Undergraduates on the medical and biomedical science degrees will benefit as the applicant includes his research in lectures on current views on vascular biology. This has the added benefit that these undergraduates are the future end users of the research.

2. Clinicians within the SouthWest London Academic Network will benefit from an increased awareness of vascular physiology and possible novel therapeutics through the Annual St George's Research Day organised by the applicant.

3. Healthcare professionals in general will benefit from this research because of the increased understanding of vascular physiology and the mechanisms of disease. They will appreciate that advancing Biomedical science leads to new treatment rationales. Findings will be disseminated to these beneficiaries through targeted press releases from the St George's media office, through attendance at Clinical meetings such as the British Hypertension Society and through collaborators Institutional-hospital communications (eg University of Copenhagen Faculty of Medical Sciences, St Thomas' London).

4. There is much interest by the Pharmaceutical Industry in Kv7 activators with the development of retigabine as a first in class anti-convulsant highlighted by the Industrial symposium on Kv7 channels held in Copenhagen in 2010, at which the applicant spoke. A number of companies have shown interest in the applicant's work because the existence of these channels in smooth muscle underlies a number of the side effects of agents such as retigabine. Pharmaceutical Companies will benefit from the findings of the research because side effects of compounds designed for neuronal disorders can be minimized through developing agents that have a greater Kv7 isoform selectivity. Moreover, new therapeutics can be developed using the same rationale but targeting the smooth muscle isoforms.

5. Charities such as the British Heart Foundation or Kidney Research UK will benefit from a better awareness of what research activity is advancing understanding of disease states. It is important that charities that support Biomedical research in the UK and gliobally appreciate that basic science does not generate a cure overnight but enhanced understanding of physiology and pathophysiology informs future healthcare procedures, pharmacological and non-pharmacological.