Cdc42 is crucial for mural cell migration, proliferation and patterning of the retinal vasculature

Aims

Mural cells constitute the outer lining of blood vessels and are essential for vascular development and function. Mural cell loss or malfunction has been associated with numerous diseases including diabetic retinopathy, stroke and amyotrophic lateral sclerosis. In this work, we investigate the role of CDC42 in mural cells in vivo, using the developing mouse retina as a model.

Methods

In this study, we generated a mouse model for Cdc42 deletion in mural cells by crossing Pdgfrb-CreER^T2 mice with Cdc42flox/flox mice. This model (Cdc42^iΔMC) allowed us to investigate the role of CDC42 in pericytes and smooth muscle cells in the developing and adult retinal vasculature.

Results

We find that, during postnatal development, CDC42 is required in both, pericytes and smooth muscle cells to maintain proper cell morphology, mural cell coverage and distribution. During retinal angiogenesis, Cdc42-depleted pericytes lag behind the sprouting front and exhibit decreased proliferation. Consequently, capillaries at the sprouting front remain pericyte deprived, become dilated and are prone to increased vascular leakage. In addition, arteries and arterioles deviate from their normal growth directions and trajectory. While in the adult retina, mural cell coverage normalizes and pericytes adopt a normal morphology, smooth muscle cell morphologies remain abnormal and arteriolar branching angles are markedly reduced.

Conclusions

Our findings demonstrate that CDC42 is required for mural cell migration and proliferation and suggest that mural cells are essential for normal morphogenesis and patterning of the developing retinal vasculature.