This extremely thin sheath acts both as an anatomical barrier and a selective filter, and its composition greatly influences the behavior of endothelial cells. The endothelium and basement membrane are in constant dialogue. In addition to supporting and structuring the vessel, the basement membrane serves as a reservoir of factors that help maintain endothelial cells in a quiescent, non-inflammatory state. The basement membrane also modulates and stabilizes endothelial energy metabolism. It serves as an interface with perivascular cells.
Endothelial cells are on the front line, exposed to circulating blood cells and soluble factors such as cytokines, hormones, metabolites, microRNAs as well as various chemicals and pathogens — i.e., environmental cues that they must continuously integrate to maintain vascular homeostasis. They detect and respond to changes in blood flow and mechanical stimuli, and control vascular tone and permeability. In the event of vessel injury, damage or defect, endothelial cells organize the response and/or repair, then eventually return to their resting state. All of these processes are guided by components of the basement membrane. Therefore, the composition of the basement membrane is tailored to the needs of the cells.
We are studying various aspects of these responses.
The angiogenic process is a typical situation in which endothelial cells undergo profound transformation alongside extensive remodeling of the basement membrane. Under the action of the angiogenic factor VEGF, cells differentiate into two distinct phenotypes through the Notch pathway. The cells that differentiate into invasive tip cells lead the way. We demonstrated that these cells form podosomes [1], which are plasma membrane, metalloprotease-rich organelles responsible for breaching the basement membrane and thereby enable endothelial cells to invade the underlying tissue [2, 3]. The process is susceptible to disruption in multiple ways during changes in the microenvironment, particularly by inflammatory stimuli [4]. Tip cells produce a new basement membrane, which for these specialized cells is selectively associated with fibrillin [5], a large glycoprotein with structural and functional properties. What is the function of fibrillin around these tip cells? How is fibrillin polymerized and organized? Which partner proteins are recruited to fibrillin in this context and for what purposes? How does fibrillin disappear when angiogenesis ends? How does the cell manage the matrix degradation by podosomes and the take-up or takeover of fibrillin actions? Could this newly revealed property of fibrillin be exploited as an application for therapeutic solutions, in order to develop molecular tools that stimulate or reduce angiogenesis? These are some of the main questions currently being studied by the team.
Fibrillin is otherwise a very well-characterized protein, but in its microfibril form, which serves as a scaffold for the deposition of elastin in the construction of elastic fibers. In the vascular system, these fibers sheath larger-caliber vessels, particularly the arterial network. In this way, fibrillin microfibrils give the vessel elasticity by enabling the assembly of elastic fibers. Beyond mechanical support, they ensure the resilience of the wall when smooth muscle cells contract and relax. We have discovered that fibrillin is also essential for the integrity of arterioles [6]. In a situation of fibrillin deficiency, gaps are observed in the smooth muscle cell layer around the arterioles, and this is associated with deterioration of the basement membrane and vascular leakage. These observations raise questions that we attempt to answer concerning how fibrillin maintains vascular cohesion, the matrix proteins with which it interacts to accomplish this task, and the signaling proteins involved in endothelial cells. They also pave the way for the development of derivatives that could compensate for decreased fibrillin levels, whether due to ageing, trauma or genetic causes [5, 7].
We explore these different questions in selected and complementary models, most often in mice, using retinopathy models for pathological angiogenesis (prematurity, diabetes) and mice carrying fibrillin gene mutations, which corresponds to Marfan syndrome in humans. We are also studying the consequences of excessive podosome formation by endothelial cells on the barrier function of the vascular basement membrane (tumor cell invasion). Translational applications of matrix supplementation approaches with recombinant products focus primarily on microvessels, with evaluation in models of cutaneous wound healing, retinal vascular arteriolar wall defects, and periodontal ligament trauma.
By analyzing how endothelial cells interact with and remodel their basement membrane, using specialized organelles and modifying the composition of their microenvironment, our work provides insight into the fundamental mechanisms that govern vascular growth, stability and repair. Our findings on the specialized roles of fibrillin—from guiding angiogenic tip cells to maintaining arteriole integrity—highlight new opportunities for therapeutic intervention. Ultimately, we aim to translate these insights into innovative strategies to restore vascular function across conditions linked to ageing, trauma, some chronic diseases or genetic defects.
