  Cells can withstand hostile environmental conditions manifest as large
mechanical forces such as pressure gradients and/or shear stresses by
dynamically changing their shape. Such conditions are realized in the Schlemm's
canal of the eye where endothelial cells that cover the inner vessel wall are
subjected to the hydrodynamic pressure gradients exerted by the aqueous humor
outflow. These cells form fluid-filled dynamic outpouchings of their basal
membrane called \textit{giant vacuoles}. The inverse of giant vacuoles are
reminiscent of cellular blebs, extracellular cytoplasmic protrusions triggered
by local temporary disruption of the contractile actomyosin cortex. Inverse
blebbing has been first observed experimentally during sprouting angiogenesis,
but its underlying physical mechanisms are poorly understood. Here, we identify
giant vacuole formation as inverse blebbing and formulate a biophysical model
of this process. Our model elucidates how cell membrane mechanical properties
affect the morphology and dynamics of giant vacuoles and predicts coarsening
akin to Ostwald ripening between multiple invaginating vacuoles. Our results
are in qualitative agreement with observations from the formation of giant
vacuoles during perfusion experiments. Our model not only elucidates the
biophysical mechanisms driving inverse blebbing and giant vacuole dynamics, but
also identifies universal features of the cellular response to pressure loads
that are relevant to many experimental contexts.
