Novel Matrix Stiffness-regulated Genes in Lymphangiogenesis and Angiogenesis

Descrizione del progetto

In mezzo scorre il fiume: la formazione dei vasi sanguigni e linfatici nella matrice extracellulare

Il sangue e la linfa scorrono nel corpo rispettivamente nei vasi sanguigni e linfatici, che formano intricate reti all’interno dei tessuti. Il sangue trasporta gas, sostanze nutritive e rifiuti metabolici, mentre il sistema linfatico drena i liquidi e le proteine in eccesso dai tessuti del corpo e li reintegra nel flusso sanguigno, impedendo il rigonfiamento. I ricercatori hanno recentemente dimostrato che la rigidità della matrice extracellulare influenza la formazione dei nuovi vasi linfatici. Grazie al sostegno del programma di azioni Marie Skłodowska-Curie, il progetto STRomA sta approfondendo il ruolo svolto dalla rigidità della matrice extracellulare nella formazione di nuovi capillari e vasi linfatici, con l’obiettivo di mettere in evidenza le somiglianze e le differenze a livello meccanicistico.

Obiettivo

Endothelial cells (ECs) recognize and respond to mechanical forces through their cell-cell and cell-matrix adhesions and translate physical stimuli into biological responses in a process called mechanotransduction. The composition and mechanical properties of the extracellular matrix (ECM) differ across the vascular tree, in its surrounding tissues and in development and diseases, such as edema formation. I have recently shown for the first time that ECM stiffness fundamentally controls lymphangiogenesis. I hypothesize that changes in ECM stiffness are a key regulatory mechanism of angiogenic processes in development and disease. A comprehensive analysis of novel ECM stiffness-regulated genes is pivotal to understand these processes integrally. In a preliminary study, I have performed differential RNA sequencing of blood (B) and lymphatic (L) ECs cultured on soft and stiff matrices. 3200 genes were regulated similarly in BECs and LECs in response to changes in matrix stiffness. Interestingly, the same number of genes was differently regulated. In the next two years, I will study the role of selected genes in lymphangiogenesis and angiogenesis in vitro and in transgenic mouse models with state-of-the-art microscope and live imaging techniques. First, I will analyze an actin-regulating protein family that is significantly regulated by matrix stiffness in both, BEC and LECs, suggesting a more general role in lymphangiogenesis and angiogenesis by regulating cytoskeletal dynamics. Second, I will study a molecule, which is involved in intracellular cGMP signaling and is predominantly regulated in LECs, suggesting a more specific role in lymphangiogenesis. Last, I will generate an in vitro fluorescent stiffness sensor to live-visualize changes in stiffness inside the EC. Ultimately, the proposed action can provide novel targets to modulate lymph and blood vessel formation with implications for edema treatment and will support me to become an independent group leader.