Yaël Nossent, PhD

My research focuses on the role of microRNAs in vascular remodelling. Vascular remodelling is a collective name for a group of physiological processes that alter blood flow and pressure via adaptive changes of the vascular wall. In general, we consider vascular remodelling as ‘positive’ when it leads to increased lumen diameter or general increases in blood flow and tissue perfusion and as ‘negative’ when it leads decreases in lumen diameter, blood flow or tissue perfusion.
I am interested in the role of vascular remodelling in occlusive arterial diseases, including myocardial infarction, ischemic stroke and peripheral arterial disease, which together are the leading cause of morbidity and mortality in both Europe and North America. These cardiovascular diseases are caused by a progressive build-up of atherosclerosis in major arteries. Atherosclerosis is defined by chronic inflammation of the vessel wall. After an initial lesion, cholesterol accumulates in the vessel wall. A so-called fatty streak is formed. Chronic inflammation in the streak leads to rearrangement of the extracellular matrix (ECM), allowing the plaque to grow in size. Rupture of a plaque causes acute artery-occluding thrombosis, known as an infarction. But even stable plaques can be symptomatic; as plaques diminish lumen size, blood flow to the downstream tissue is decreased, causing pain, especially during exercise (angina pectoris and claudication), or even at rest (critical ischemia).
Severe atherosclerosis requires interventional treatment with endovascular procedures or bypass surgery, to restore blood flow. Tissue damage inflicted by these procedures leads to accelerated atherosclerosis and intimal hyperplasia resulting in rapid restenosis of the artery in approximately 50% of patients. As re-intervention often proves impossible due to deteriorated condition of the vessels, novel drugs that effectively prevent restenosis would have a major impact on lowering morbidity and mortality associated with occlusive arterial disease.
Our body has two natural repair mechanisms to recover blood flow, namely angiogenesis and arteriogenesis. Angiogenesis is defined by sprouting of small capillaries from existing vessels in the microcirculation. An ischemic signal triggers nearby vascular endothelial cells to form sprouts towards the ischemic area. Ischemia-induced inflammation enables rearrangement of the ECM, providing space for the sprouts to grow. Arteriogenesis is defined as the development and maturation of collateral arteries from a pre-existing arteriole network. Arteriogenesis is triggered by increased shear stress and subsequent inflammatory processes in arterioles. Under healthy conditions, blood-flow through the arteriole network is extremely low. But when an upstream artery becomes occluded, blood is redirected through the arterioles, drastically increasing fluid shear stress on the arteriole wall, triggering an inflammatory response. As in atherosclerosis and angiogenesis, inflammation-induced rearrangement of the ECM allows for vessel growth. Other than in atherosclerosis however, arterioles remodel outward, increasing lumen diameter. The subsequent decrease in fluid shear stress results in cessation of the arteriogenic process.
Even though together, angiogenesis and arteriogenesis could lead to full recovery of severe occlusive arterial disease, it becomes painfully clear that both processes share many common denominators with atherosclerosis and restenosis. Indeed, factors that contribute to effective neovascularisation, often also contribute to plaque progression and restenosis.
This is generally referred to as the Janus-phenomenon, after the two-faced Roman god Janus. The Janus-phenomenon can obviously cause problems when we try to induce neovascularisation in patients with occlusive arterial disease, particularly after endovascular or surgical interventions.
To discriminate between positive and negative remodelling, we need to thoroughly understand regulatory networks underlying vascular remodelling. I believe that microRNAs play a crucial role in regulation of vascular remodelling. MicroRNAs are small single-stranded (~20b) endogenous RNA molecules that bind the 3’UTR of their target genes, up to several hundreds for a single microRNA, to inhibit translation, thereby decreasing and fine-tuning expression levels of these target genes. Over the past few years, it has been shown that microRNAs play a crucial role in cardiovascular disease. We were among the first to show that changes in microRNA-target gene binding impact the risk of cardiovascular disease in humans.
We recently discovered that a particular group of microRNAs plays an important regulatory role in vascular remodelling. Most microRNAs in the cluster influence both positive and negative remodelling in a similar manner, conform the Janus phenomenon. However, we found certain microRNAs in the cluster have differential effects on positive and negative remodelling. My research aims to target these specific microRNAs in order to inhibit atherosclerosis and restenosis and simultaneously stimulate neovascularisation in patients with occlusive arterial disease for the first time.