Dysfunctional Mechanotransduction Regulates the Progression of PIK3CA-driven Vascular Malformations

Overview

Journal APL Bioeng

Date 2025 Feb 12

PMID 39935869

Authors

Wen Yih Aw

Aanya Sawhney

Mitesh Rathod

Chloe P Whitworth

Elizabeth L Doherty

Ethan Madden

Jingming Lu

Kaden Westphal

Ryan Stack

William J Polacheck

Affiliations

Soon will be listed here.

Abstract

Somatic activating mutations in are common drivers of vascular and lymphatic malformations. Despite common biophysical signatures of tissues susceptible to lesion formation, including compliant extracellular matrix and low rates of perfusion, lesions vary in clinical presentation from localized cystic dilatation to diffuse and infiltrative vascular dysplasia. The mechanisms driving the differences in disease severity and variability in clinical presentation and the role of the biophysical microenvironment in potentiating progression are poorly understood. Here, we investigate the role of hemodynamic forces and the biophysical microenvironment in the pathophysiology of vascular malformations (VMs), and we identify hemodynamic shear stress and defective endothelial cell mechanotransduction as key regulators of lesion progression. We found that constitutive PI3K activation impaired flow-mediated endothelial cell alignment and barrier function. We show that defective shear stress sensing in endothelial cells is associated with reduced myosin light chain phosphorylation, junctional instability, and defective recruitment of vinculin to cell-cell junctions. Using three dimensional (3D) microfluidic models of the vasculature, we demonstrate that microvessels apply reduced traction forces and are unaffected by flow interruption. We further found that draining transmural flow resulted in increased sprouting and invasion responses in microvessels. Mechanistically, constitutive PI3K activation decreased cellular and nuclear elasticity resulting in defective cellular tensional homeostasis in endothelial cells which may underlie vascular dilation, tissue hyperplasia, and hypersprouting in -driven venous and lymphatic malformations. Together, these results suggest that defective nuclear mechanics, impaired cellular mechanotransduction, and maladaptive hemodynamic responses contribute to the development and progression of -driven vascular malformations.

References

Weber G, Parat M, Binder Z, Gallia G, Riggins G . Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells. Oncotarget. 2011; 2(11):833-49. PMC: 3260001. DOI: 10.18632/oncotarget.346. View

Chen Q, Jiang L, Li C, Hu D, Bu J, Cai D . Haemodynamics-driven developmental pruning of brain vasculature in zebrafish. PLoS Biol. 2012; 10(8):e1001374. PMC: 3419171. DOI: 10.1371/journal.pbio.1001374. View

Aw W, Cho C, Wang H, Cooper A, Doherty E, Rocco D . Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation. Sci Adv. 2023; 9(7):eade8939. PMC: 9931220. DOI: 10.1126/sciadv.ade8939. View

Huo R, Yang Y, Sun Y, Zhou Q, Zhao S, Mo Z . Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation. Angiogenesis. 2023; 26(2):295-312. DOI: 10.1007/s10456-023-09866-9. View

Conway D, Coon B, Budatha M, Arsenovic P, Orsenigo F, Wessel F . VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. Curr Biol. 2017; 27(14):2219-2225.e5. PMC: 5667920. DOI: 10.1016/j.cub.2017.06.020. View

Herbert S, Huisken J, Kim T, Feldman M, Houseman B, Wang R . Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation. Science. 2009; 326(5950):294-8. PMC: 2865998. DOI: 10.1126/science.1178577. View

Salek M, Sattari P, Martinuzzi R . Analysis of fluid flow and wall shear stress patterns inside partially filled agitated culture well plates. Ann Biomed Eng. 2011; 40(3):707-28. DOI: 10.1007/s10439-011-0444-9. View

Abe K, Takeichi M . EPLIN mediates linkage of the cadherin catenin complex to F-actin and stabilizes the circumferential actin belt. Proc Natl Acad Sci U S A. 2007; 105(1):13-9. PMC: 2224173. DOI: 10.1073/pnas.0710504105. View

Hong T, Xiao X, Ren J, Cui B, Zong Y, Zou J . Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations. Brain. 2021; 144(9):2648-2658. DOI: 10.1093/brain/awab117. View

10.

Song J, Munn L . Fluid forces control endothelial sprouting. Proc Natl Acad Sci U S A. 2011; 108(37):15342-7. PMC: 3174629. DOI: 10.1073/pnas.1105316108. View

11.

Bi L, Okabe I, Bernard D, Wynshaw-Boris A, Nussbaum R . Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem. 1999; 274(16):10963-8. DOI: 10.1074/jbc.274.16.10963. View

12.

Gimbrone Jr M, Topper J, Nagel T, Anderson K, Garcia-Cardena G . Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci. 2000; 902:230-9; discussion 239-40. DOI: 10.1111/j.1749-6632.2000.tb06318.x. View

13.

Secomb T, Alberding J, Hsu R, Dewhirst M, Pries A . Angiogenesis: an adaptive dynamic biological patterning problem. PLoS Comput Biol. 2013; 9(3):e1002983. PMC: 3605064. DOI: 10.1371/journal.pcbi.1002983. View

14.

Wiig H, Swartz M . Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol Rev. 2012; 92(3):1005-60. DOI: 10.1152/physrev.00037.2011. View

15.

Vickerman V, Kamm R . Mechanism of a flow-gated angiogenesis switch: early signaling events at cell-matrix and cell-cell junctions. Integr Biol (Camb). 2012; 4(8):863-74. PMC: 4090039. DOI: 10.1039/c2ib00184e. View

16.

Coon B, Baeyens N, Han J, Budatha M, Ross T, Fang J . Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex. J Cell Biol. 2015; 208(7):975-86. PMC: 4384728. DOI: 10.1083/jcb.201408103. View

17.

Bertocchi C, Wang Y, Ravasio A, Hara Y, Wu Y, Sailov T . Nanoscale architecture of cadherin-based cell adhesions. Nat Cell Biol. 2016; 19(1):28-37. PMC: 5421576. DOI: 10.1038/ncb3456. View

18.

Huang D, Bax N, Buckley C, Weis W, Dunn A . Vinculin forms a directionally asymmetric catch bond with F-actin. Science. 2017; 357(6352):703-706. PMC: 5821505. DOI: 10.1126/science.aan2556. View

19.

Angulo-Urarte A, Casado P, Castillo S, Kobialka P, Kotini M, Figueiredo A . Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility. Nat Commun. 2018; 9(1):4826. PMC: 6240100. DOI: 10.1038/s41467-018-07172-3. View

20.

Queisser A, Boon L, Vikkula M . Etiology and Genetics of Congenital Vascular Lesions. Otolaryngol Clin North Am. 2017; 51(1):41-53. DOI: 10.1016/j.otc.2017.09.006. View