PDGFD-induced pericyte contractility drives pathological neoangiogenesis
- 1Universidade Catolica Portuguesa
Abstract
Neovascular tufts (NVTs) are a defining feature of proliferative retinopathies such as diabetic retinopathy and retinopathy of prematurity, in which they compromise retinal integrity and vision. Excessive endothelial cell (EC) sprouting underlies their formation, yet the cellular and mechanical mechanisms that shape NVTs, and the contribution of pericytes (PCs) to this process, remain unclear. In this work, we investigated the role of actomyosin contractility in ECs and PCs during pathological angiogenesis and NVT formation. We identified non-muscle myosin IIA (NMIIA) and phosphorylated myosin light chains (MLCs) as a key signature of PCs and ECs in retinopathy and NVTs. Using inducible deletion of Myh9 in the oxygen-induced retinopathy mouse model, we uncover distinct and opposing roles for NMIIA in the two cell types. Endothelial NMIIA promotes neovascularisation and prevents enlargement of NVTs, whilst PC NMIIA drives neovascular tuft formation. Mechanistically, we identify platelet-derived growth factor D (PDGFD), but not PDGFB, as a driver of pathological PC actomyosin contractility through Rho-associated coiled-coil kinase (ROCK). Genetic deletion of Pdgfd partially phenocopies the loss of NMIIA in PCs, reducing NVT formation and lowering NMIIA and phosphorylated MLC levels within NVTs. Our findings establish cell-type-specific actomyosin contractility as a determinant of NVT pathogenesis and identify PDGFD-ROCK-NMIIA signalling in PCs as a therapeutic target in proliferative retinopathies.
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BibTeX
@misc{pena2026pdgfdinduced,
title = {{PDGFD-induced pericyte contractility drives pathological neoangiogenesis}},
author = {A. Pena and L. H. Misikova and Y. Jin and M. P. Saraiva and D. Ramalho and C. Esteves and M. Ouarne and M. Martins and Y. Carvalho and E. B. Folestad and U. Eriksson and L. Jakobsson and A. M. Figueiredo and C. A. Franco},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.762436},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.762436v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - PDGFD-induced pericyte contractility drives pathological neoangiogenesis
AU - A. Pena
AU - L. H. Misikova
AU - Y. Jin
AU - M. P. Saraiva
AU - D. Ramalho
AU - C. Esteves
AU - M. Ouarne
AU - M. Martins
AU - Y. Carvalho
AU - E. B. Folestad
AU - U. Eriksson
AU - L. Jakobsson
AU - A. M. Figueiredo
AU - C. A. Franco
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.762436
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.762436v1
AB - Neovascular tufts (NVTs) are a defining feature of proliferative retinopathies such as diabetic retinopathy and retinopathy of prematurity, in which they compromise retinal integrity and vision. Excessive endothelial cell (EC) sprouting underlies their formation, yet the cellular and mechanical mechanisms that shape NVTs, and the contribution of pericytes (PCs) to this process, remain unclear. In this work, we investigated the role of actomyosin contractility in ECs and PCs during pathological angiogenesis and NVT formation. We identified non-muscle myosin IIA (NMIIA) and phosphorylated myosin light chains (MLCs) as a key signature of PCs and ECs in retinopathy and NVTs. Using inducible deletion of Myh9 in the oxygen-induced retinopathy mouse model, we uncover distinct and opposing roles for NMIIA in the two cell types. Endothelial NMIIA promotes neovascularisation and prevents enlargement of NVTs, whilst PC NMIIA drives neovascular tuft formation. Mechanistically, we identify platelet-derived growth factor D (PDGFD), but not PDGFB, as a driver of pathological PC actomyosin contractility through Rho-associated coiled-coil kinase (ROCK). Genetic deletion of Pdgfd partially phenocopies the loss of NMIIA in PCs, reducing NVT formation and lowering NMIIA and phosphorylated MLC levels within NVTs. Our findings establish cell-type-specific actomyosin contractility as a determinant of NVT pathogenesis and identify PDGFD-ROCK-NMIIA signalling in PCs as a therapeutic target in proliferative retinopathies.
ER -