Prof. Dr. Paul Quax

Short-term preoperative methionine restriction (MetR) is a promising translatable strategy to mitigate surgical injury response. However, its application to improve post-interventional vascular remodeling remains underexplored. Here we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and pathologic vascular remodeling following vein graft surgery in male mice. RNA sequencing reveals that MetR enhances browning in arterial (thoracic aorta) perivascular adipose tissue (PVAT) and induces it in venous (caval vein) PVAT. Specifically, Ppara is highly upregulated in PVAT-adipocytes upon MetR. Furthermore, MetR dampens the postoperative pro-inflammatory response to surgery in PVAT-macrophages in vivo and in vitro. This study shows that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in MetR-induced browning of PVAT. Furthermore, we demonstrate the potential of short-term preoperative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.

Intracranial atherosclerosis is one of the most common causes of ischaemic stroke. However, there is a substantial knowledge gap on the development of intracranial atherosclerosis. Intracranial arteries are characterized by an upregulation of tight junctions between endothelial cells, which control endothelial permeability. We investigated the role of N6-methyladenosine (m6A), a common RNA modification, on endothelial integrity, focusing on the pro-atherogenic microRNA miR-494-3p and tight junction proteins TJP1 and PECAM1.

Vascular remodeling is a very general feature related to angiogenesis and arteriogenesis, which are involved in neovascularization processes [...].

Intraplaque angiogenesis occurs in response to atherosclerotic plaque hypoxia, which is driven mainly by highly metabolically active macrophages. Improving plaque oxygenation by increasing macrophage hypoxic signaling, thus stimulating intraplaque angiogenesis, could restore cellular function and neovessel maturation, and decrease plaque formation. Prolyl hydroxylases (PHDs) regulate cellular responses to hypoxia. We therefore aimed to elucidate the role of myeloid PHD2, the dominant PHD isoform, on intraplaque angiogenesis in a murine model for venous bypass grafting.

Chronic limb-threatening ischemia (CLTI) is a critical end-stage disease that leads to high amputation rates. Over the past few decades, therapeutic angiogenesis has attracted a lot of attention as a means to reduce the necessity for amputations. Especially gene- and cell therapy are regarded to as possible treatment modalities to restore the hampered blood flow. So far, early-phase clinical trials often fail to prove a significant clinical improvement in mortality, amputation rate, and ulcer healing but still conclude that therapeutic angiogenesis might be promising as therapy. The subsequent phase III clinical trials based on these indecisive early trials fail consistently to demonstrate clinical benefits leaving the promising early results unvalidated. In this review we will illustrate that designing good trials for CLTI patients is challenging, not in the last place since patients are often not eligible due to strict inclusion criteria. Moreover, in this review, we advocate that clinical trials should be conducted with a low risk of bias and that it is of utmost importance to publish results, regardless of the outcome. It is definitely very concerning that many studies of a lower quality (due to small group size or high chance for bias) reporting positive outcomes are published while good quality trials (often with larger group sizes) are stopped prematurely due to lack of effects and remain unpublished. This keeps the 'promising but not yet proven' image of these therapeutic neovascularization studies alive, with still new groups starting similar trials.