Rho GTPase Signaling in Endothelial Cell Biology

Rho GTPases constitute a family of molecular switches that regulate the actin cytoskeleton, membrane trafficking and gene expression in endothelial cells, thereby orchestrating vascular homeostasis, permeability and new vessel formation. Upon binding GTP, family members such as RhoA, Rac1, Cdc42 and the endothelium-enriched RhoJ adopt active conformations that engage downstream effectors including Rho-associated protein kinases and p21-activated kinases. These cascades drive stress fibre assembly, lamellipodial and filopodial protrusions, cell–cell junction remodelling and trans-endothelial migration of leukocytes. The dynamic balance of Rho GTPase activities underpins the quiescent barrier properties of the endothelium and its rapid reprogramming during angiogenesis and inflammatory responses. In pathological states such as tumour neovascularisation, diabetic retinopathy and atherosclerosis, dysregulated Rho GTPase signalling leads to aberrant vessel sprouting, barrier breakdown and altered extracellular matrix remodelling. A nuanced understanding of the spatiotemporal control of GTP/GDP cycling by guanine nucleotide exchange factors, GTPase-activating proteins and lipid-mediated membrane localisation has revealed new targets for therapeutic modulation of vascular dysfunction.

Research from Nature Portfolio

Recent studies have illuminated the context-dependent role of endothelial RhoA in angiogenic processes. In vitro analyses demonstrate that RhoA activation is essential for endothelial proliferation, directed migration and three-dimensional tube formation in response to vascular endothelial growth factor and sphingosine-1-phosphate. Surprisingly, genetic deletion of endothelial RhoA in murine models produces only modest defects in physiological angiogenesis, indicating the existence of compensatory signalling routes in vivo. These findings underscore a differential requirement for RhoA in homeostatic versus stimulatory conditions and suggest that selective inhibition of RhoA may modulate pathological angiogenesis without compromising normal vessel integrity.

Rho GTPase Signaling in Endothelial Cell Biology publication trend

The graph below shows the total number of articles in rho gtpase signaling in endothelial cell biology across all publications each year (not limited to Nature Index journals).

Technical terms

Rho GTPase: A small G-protein that cycles between inactive GDP-bound and active GTP-bound states to regulate cytoskeletal and signalling pathways.

Endothelial cell: A vascular lining cell that controls blood–tissue exchange, angiogenesis and barrier function.

Angiogenesis: The formation of new blood vessels from pre-existing vasculature, essential for development, wound healing and tumour growth.

Cytoskeleton: A network of actin filaments and microtubules that determines cell shape, polarity and motility.

Guanine nucleotide exchange factor (GEF): A protein that promotes the exchange of GDP for GTP to activate GTPases.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can modulate signalling pathways and redox homeostasis.

References

1. The antiangiogenic effect of digitoxin is dependent on a ROS-elicited RhoA/ROCK pathway activation. Biochemical Pharmacology (2024).
2. Actin cytoskeleton in angiogenesis. Biology Open (2022).
3. A functional antagonism between RhoJ and Cdc42 regulates fibronectin remodelling during angiogenesis. Small GTPases (2020).
4. Endothelial RhoA GTPase is essential for in vitro endothelial functions but dispensable for physiological in vivo angiogenesis. Scientific Reports (2019).