Blood vessels form extensive vascular networks allowing an efficient transport of gases, fluids and nutrients for all tissues. Sprouting angiogenesis generates new blood vessels during embryonic development and adult. Dysfunctional, either excessive or insufficient, angiogenesis is a cause of several vascular diseases, such as ischemia, arteriovenous malformations, tumor angiogenesis, and diabetic retinopathy.
During sprouting angiogenesis, endothelial tip cells are highly migratory and guide the trailing endothelial stalk cells in the nascent sprout towards the source of pro-angiogenic factors. However, the mechanisms regulating the actin cytoskeleton contributing to the motility and invasive proprieties of endothelial tip cells are poorly understood. Serum response factor (SRF) is a transcription factor that regulates expression of genes encoding cytoskeletal proteins. SRF, together with its cofactors [myocardin related transcription factors (MRTFs)], is essential for tip cell migration and invasion during sprouting angiogenesis. But which genes downstream of SRF/MRTF signaling are central in this process are completely not characterized.
Based on a microarray approach, we defined the MRTF/SRF-dependent transcriptome of endothelial cells. Using a combination of multiple in silico and in vitro approaches, we identified the relevant genes downstream of SRF signaling, and we characterize their function in cell migration and cytoarchitecture of endothelial cells. From our analysis, inhibition of MYH9, the gene coding for myosin IIA heavy chain (NMII-A), reproduced alone the full spectrum of phenotypes presented in MRTF/SRF-deficient endothelium, and regulates tip cell motility and invasion. Interestingly, we found a specialized localization of MYH9 in endothelial tip cells, pointing towards an important and novel role in filopodia formation and/or stability.
Our research provides new insights on the biology of endothelial tip cells, which can be a first step towards new therapeutic approaches targeting pathological vascularization
