Research progress of matrix stiffness in regulating endothelial cell sprouting_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

CHEN Qiyu ¹ , WANG Wen ^1,2 , YUAN Changyong ^1,3 ,  WANG Penglai ^1,3

1. School of Stomatology, Xuzhou Medical University, Xuzhou Jiangsu, 221004, P. R. China;
2. Department of Periodontology, Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou Jiangsu, 221002, P. R. China;
3. Department of Oral Implantology, Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou Jiangsu, 221002, P. R. China;

Corresponding author：

WANG Penglai, Email: jessicachan08@163.com

Keywords：

Matrix stiffness; endothelial cells; sprouting; angiogenesis; mechanism; tissue engineering

DOI：

10.7507/1002-1892.202210019

Video：

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Objective To review the research progress on the role and mechanism of matrix stiffness in regulating endothelial cell sprouting. Methods The related literature at home and abroad in recent years was extensively reviewed, and the behaviors of matrix stiffness related endothelial cell sprouting in different cell cultivation conditions were analyzed, and the specific molecular mechanism of matrix stiffness regulating related signal pathways in endothelial cell sprouting was elaborated. Results In two-dimensional cell cultivation condition, increase of matrix stiffness stimulates endothelial cell sprouting within a certain range. However, in three-dimensional cell cultivation condition, the detailed function of matrix stiffness in regulating endothelial cell sprouting and angiogenesis are still unclear. At present, the research of the related molecular mechanism mainly focuses on YAP/TAZ, and roles of its upstream and downstream signal molecules. Matrix stiffness can regulate endothelial cell sprouting by activating or inhibiting signal pathways to participate in vascularization. Conclusion Matrix stiffness plays a vital role in regulating endothelial cell sprouting, but its specific role and molecular mechanism in different environments remain ambiguous and need further study.

Citation： CHEN Qiyu, WANG Wen, YUAN Changyong, WANG Penglai. Research progress of matrix stiffness in regulating endothelial cell sprouting. Chinese Journal of Reparative and Reconstructive Surgery, 2023, 37(2): 202-207. doi: 10.7507/1002-1892.202210019 Copy

1.	Simunovic F, Finkenzeller G. Vascularization strategies in bone tissue engineering. Cells, 2021, 10(7): 1749. doi: 10.3390/cells10071749.
2.	Laschke MW, Menger MD. Spheroids as vascularization units: From angiogenesis research to tissue engineering applications. Biotechnol Adv, 2017, 35(6): 782-791.
3.	Hou T, Du M, Gao X, et al. Human vascular endothelial cells promote the secretion of vascularization factors and migration of human skin fibroblasts under co-culture and its preliminary application. Int J Mol Sci, 2022, 23(22): 13995. doi: 10.3390/ijms232213995.
4.	Zhao W, Zhu J, Hang J, et al. Biomaterials to promote vascularization in tissue engineering organs and ischemic fibrotic diseases. MedComm-Biomaterials and Applications, 2022, 1(1): e16. doi: 10.1002/mba2.16.
5.	Usuba R, Pauty J, Soncin F, et al. EGFL7 regulates sprouting angiogenesis and endothelial integrity in a human blood vessel model. Biomaterials, 2019, 197: 305-316.
6.	Kim J, Kim YH, Kim J, et al. YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J Clin Invest, 2017, 127(9): 3441-3461.
7.	Abdalrahman T, Checa S. On the role of mechanical signals on sprouting angiogenesis through computer modeling approaches. Biomech Model Mechanobiol, 2022, 21(6): 1623-1640.
8.	Link PA, Heise RL, Weinberg SH. Cellular mitosis predicts vessel stability in a mechanochemical model of sprouting angiogenesis. Biomech Model Mechanobiol, 2021, 20(3): 1195-1208.
9.	Heitzig N, Brinkmann BF, Koerdt SN, et al. Annexin A8 promotes VEGF-A driven endothelial cell sprouting. Cell Adh Migr, 2017, 11(3): 275-287.
10.	Guo Y, Mei F, Huang Y, et al. Matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP signaling axis. Bioact Mater, 2021, 7: 364-376.
11.	Chen W, Xia P, Wang H, et al. The endothelial tip-stalk cell selection and shuffling during angiogenesis. J Cell Commun Signal, 2019, 13(3): 291-301.
12.	Kim YH, Choi J, Yang MJ, et al. A MST1-FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis. Nat Commun, 2019, 10(1): 838. doi: 10.1038/s41467-019-08773-2.
13.	姚牧笛, 孙婷婷, 蒋沁. 血管内皮细胞在视网膜出芽式血管生成中的作用及其调控机制. 国际眼科杂志, 2020, 20(2): 251-254.
14.	Bandaru P, Cefaloni G, Vajhadin F, et al. Mechanical cues regulating proangiogenic potential of human mesenchymal stem cells through YAP-mediated mechanosensing. Small, 2020, 16(25): e2001837. doi: 10.1002/smll.202001837.
15.	Romero-López M, Trinh AL, Sobrino A, et al. Recapitulating the human tumor microenvironment: Colon tumor-derived extracellular matrix promotes angiogenesis and tumor cell growth. Biomaterials, 2017, 116: 118-129.
16.	Zhao D, Xue C, Li Q, et al. Substrate stiffness regulated migration and angiogenesis potential of A549 cells and HUVECs. J Cell Physiol, 2018, 233(4): 3407-3417.
17.	Martínez GF, Fagetti J, Vierci G, et al. Extracellular matrix stiffness negatively affects axon elongation, growth cone area and F-actin levels in a collagen type Ⅰ 3D culture. J Tissue Eng Regen Med, 2022, 16(2): 151-162.
18.	Yun S, Hu R, Schwaemmle ME, et al. Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis. J Clin Invest, 2019, 129(11): 4863-4874.
19.	Yeh YT, Hur SS, Chang J, et al. Matrix stiffness regulates endothelial cell proliferation through septin 9. PLoS One, 2012, 7(10): e46889. doi: 10.1371/journal.pone.0046889.
20.	Liu Y, Lv J, Liang X, et al. Fibrin stiffness mediates dormancy of tumor-repopulating cells via a Cdc42-driven Tet2 epigenetic program. Cancer Res, 2018, 78(14): 3926-3937.
21.	陈伟洋, 田俊, 韦曦. 硅离子在骨组织修复再生领域的作用. 中华口腔医学研究杂志 (电子版), 2021, 15(6): 375-381.
22.	Fu P, Ramchandran R, Shaaya M, et al. Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation. J Biol Chem, 2020, 295(22): 7669-7685.
23.	Bordeleau F, Mason BN, Lollis EM, et al. Matrix stiffening promotes a tumor vasculature phenotype. Proc Natl Acad Sci U S A, 2017, 114(3): 492-497.
24.	Wang Y, Zhang X, Wang W, et al. Integrin αVβ5/Akt/Sp1 pathway participates in matrix stiffness-mediated effects on VEGFR2 upregulation in vascular endothelial cells. Am J Cancer Res, 2020, 10(8): 2635-2648.
25.	Colombo E, Cattaneo MG. Multicellular 3D models to study tumour-stroma interactions. Int J Mol Sci, 2021, 22(4): 1633. doi: 10.3390/ijms22041633.
26.	Berger AJ, Renner CM, Hale I, et al. Scaffold stiffness influences breast cancer cell invasion via EGFR-linked Mena upregulation and matrix remodeling. Matrix Biol, 2020, 85-86: 80-93.
27.	Berger AJ, Linsmeier KM, Kreeger PK, et al. Decoupling the effects of stiffness and fiber density on cellular behaviors via an interpenetrating network of gelatin-methacrylate and collagen. Biomaterials, 2017, 141: 125-135.
28.	Bao M, Chen Y, Liu JT, et al. Extracellular matrix stiffness controls VEGF165 secretion and neuroblastoma angiogenesis via the YAP/RUNX2/SRSF1 axis. Angiogenesis, 2022, 25(1): 71-86.
29.	Gonçalves IG, Garcia-Aznar JM. Extracellular matrix density regulates the formation of tumour spheroids through cell migration. PLoS Comput Biol, 2021, 17(2): e1008764. doi: 10.1371/journal.pcbi.1008764.
30.	Wang X, Freire Valls A, Schermann G, et al. YAP/TAZ orchestrate VEGF signaling during developmental angiogenesis. Dev Cell, 2017, 42(5): 462-478.
31.	Jiang X, Hu J, Wu Z, et al. Protein phosphatase 2A mediates YAP activation in endothelial cells upon VEGF stimulation and matrix stiffness. Front Cell Dev Biol, 2021, 9: 675562. doi: 10.3389/fcell.2021.675562.
32.	Nakajima H, Yamamoto K, Agarwala S, et al. Flow-dependent endothelial YAP regulation contributes to vessel maintenance. Dev Cell, 2017, 40(6): 523-536.
33.	Shen Y, Wang X, Lu J, et al. Reduction of liver metastasis stiffness improves response to bevacizumab in metastatic colorectal cancer. Cancer Cell, 2020, 37(6): 800-817.
34.	Barreto S, Gonzalez-Vazquez A, Cameron AR, et al. Identification of the mechanisms by which age alters the mechanosensitivity of mesenchymal stromal cells on substrates of differing stiffness: Implications for osteogenesis and angiogenesis. Acta Biomater, 2017, 53: 59-69.
35.	Xie J, Zhang D, Ling Y, et al. Substrate elasticity regulates vascular endothelial growth factor A (VEGFA) expression in adipose-derived stromal cells: Implications for potential angiogenesis. Colloids Surf B Biointerfaces, 2019, 175: 576-585.
36.	Landau S, Ben-Shaul S, Levenberg S. Oscillatory train promotes vessel stabilization and alignment through fibroblast YAP-mediated mechanosensitivity. Adv Sci (Weinh), 2018, 5(9): 1800506. doi: 10.1002/advs.201800506.
37.	Sack KD, Teran M, Nugent MA. Extracellular matrix stiffness controls VEGF signaling and processing in endothelial cells. J Cell Physiol, 2016, 231(9): 2026-2039.
38.	Miller B, Sewell-Loftin MK. Mechanoregulation of vascular endothelial growth factor receptor 2 in angiogenesis. Front Cardiovasc Med, 2022, 8: 804934. doi: 10.3389/fcvm.2021.804934.
39.	van der Stoel M, Schimmel L, Nawaz K, et al. DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis. J Cell Sci, 2020, 133(3): jcs239947. doi: 10.1242/jcs.239947.
40.	Kai F, Laklai H, Weaver VM. Force matters: Biomechanical regulation of cell invasion and migration in disease. Trends Cell Biol, 2016, 26(7): 486-497.
41.	Francis CR, Kincross H, Kushner EJ. Rab35 governs apicobasal polarity through regulation of actin dynamics during sprouting angiogenesis. Nat Commun, 2022, 13(1): 5276. doi: 10.1038/s41467-022-32853-5.

1. Simunovic F, Finkenzeller G. Vascularization strategies in bone tissue engineering. Cells, 2021, 10(7): 1749. doi: 10.3390/cells10071749.
2. Laschke MW, Menger MD. Spheroids as vascularization units: From angiogenesis research to tissue engineering applications. Biotechnol Adv, 2017, 35(6): 782-791.
3. Hou T, Du M, Gao X, et al. Human vascular endothelial cells promote the secretion of vascularization factors and migration of human skin fibroblasts under co-culture and its preliminary application. Int J Mol Sci, 2022, 23(22): 13995. doi: 10.3390/ijms232213995.
4. Zhao W, Zhu J, Hang J, et al. Biomaterials to promote vascularization in tissue engineering organs and ischemic fibrotic diseases. MedComm-Biomaterials and Applications, 2022, 1(1): e16. doi: 10.1002/mba2.16.
5. Usuba R, Pauty J, Soncin F, et al. EGFL7 regulates sprouting angiogenesis and endothelial integrity in a human blood vessel model. Biomaterials, 2019, 197: 305-316.
6. Kim J, Kim YH, Kim J, et al. YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J Clin Invest, 2017, 127(9): 3441-3461.
7. Abdalrahman T, Checa S. On the role of mechanical signals on sprouting angiogenesis through computer modeling approaches. Biomech Model Mechanobiol, 2022, 21(6): 1623-1640.
8. Link PA, Heise RL, Weinberg SH. Cellular mitosis predicts vessel stability in a mechanochemical model of sprouting angiogenesis. Biomech Model Mechanobiol, 2021, 20(3): 1195-1208.
9. Heitzig N, Brinkmann BF, Koerdt SN, et al. Annexin A8 promotes VEGF-A driven endothelial cell sprouting. Cell Adh Migr, 2017, 11(3): 275-287.
10. Guo Y, Mei F, Huang Y, et al. Matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP signaling axis. Bioact Mater, 2021, 7: 364-376.
11. Chen W, Xia P, Wang H, et al. The endothelial tip-stalk cell selection and shuffling during angiogenesis. J Cell Commun Signal, 2019, 13(3): 291-301.
12. Kim YH, Choi J, Yang MJ, et al. A MST1-FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis. Nat Commun, 2019, 10(1): 838. doi: 10.1038/s41467-019-08773-2.
13. 姚牧笛, 孙婷婷, 蒋沁. 血管内皮细胞在视网膜出芽式血管生成中的作用及其调控机制. 国际眼科杂志, 2020, 20(2): 251-254.
14. Bandaru P, Cefaloni G, Vajhadin F, et al. Mechanical cues regulating proangiogenic potential of human mesenchymal stem cells through YAP-mediated mechanosensing. Small, 2020, 16(25): e2001837. doi: 10.1002/smll.202001837.
15. Romero-López M, Trinh AL, Sobrino A, et al. Recapitulating the human tumor microenvironment: Colon tumor-derived extracellular matrix promotes angiogenesis and tumor cell growth. Biomaterials, 2017, 116: 118-129.
16. Zhao D, Xue C, Li Q, et al. Substrate stiffness regulated migration and angiogenesis potential of A549 cells and HUVECs. J Cell Physiol, 2018, 233(4): 3407-3417.
17. Martínez GF, Fagetti J, Vierci G, et al. Extracellular matrix stiffness negatively affects axon elongation, growth cone area and F-actin levels in a collagen type Ⅰ 3D culture. J Tissue Eng Regen Med, 2022, 16(2): 151-162.
18. Yun S, Hu R, Schwaemmle ME, et al. Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis. J Clin Invest, 2019, 129(11): 4863-4874.
19. Yeh YT, Hur SS, Chang J, et al. Matrix stiffness regulates endothelial cell proliferation through septin 9. PLoS One, 2012, 7(10): e46889. doi: 10.1371/journal.pone.0046889.
20. Liu Y, Lv J, Liang X, et al. Fibrin stiffness mediates dormancy of tumor-repopulating cells via a Cdc42-driven Tet2 epigenetic program. Cancer Res, 2018, 78(14): 3926-3937.
21. 陈伟洋, 田俊, 韦曦. 硅离子在骨组织修复再生领域的作用. 中华口腔医学研究杂志 (电子版), 2021, 15(6): 375-381.
22. Fu P, Ramchandran R, Shaaya M, et al. Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation. J Biol Chem, 2020, 295(22): 7669-7685.
23. Bordeleau F, Mason BN, Lollis EM, et al. Matrix stiffening promotes a tumor vasculature phenotype. Proc Natl Acad Sci U S A, 2017, 114(3): 492-497.
24. Wang Y, Zhang X, Wang W, et al. Integrin αVβ5/Akt/Sp1 pathway participates in matrix stiffness-mediated effects on VEGFR2 upregulation in vascular endothelial cells. Am J Cancer Res, 2020, 10(8): 2635-2648.
25. Colombo E, Cattaneo MG. Multicellular 3D models to study tumour-stroma interactions. Int J Mol Sci, 2021, 22(4): 1633. doi: 10.3390/ijms22041633.
26. Berger AJ, Renner CM, Hale I, et al. Scaffold stiffness influences breast cancer cell invasion via EGFR-linked Mena upregulation and matrix remodeling. Matrix Biol, 2020, 85-86: 80-93.
27. Berger AJ, Linsmeier KM, Kreeger PK, et al. Decoupling the effects of stiffness and fiber density on cellular behaviors via an interpenetrating network of gelatin-methacrylate and collagen. Biomaterials, 2017, 141: 125-135.
28. Bao M, Chen Y, Liu JT, et al. Extracellular matrix stiffness controls VEGF165 secretion and neuroblastoma angiogenesis via the YAP/RUNX2/SRSF1 axis. Angiogenesis, 2022, 25(1): 71-86.
29. Gonçalves IG, Garcia-Aznar JM. Extracellular matrix density regulates the formation of tumour spheroids through cell migration. PLoS Comput Biol, 2021, 17(2): e1008764. doi: 10.1371/journal.pcbi.1008764.
30. Wang X, Freire Valls A, Schermann G, et al. YAP/TAZ orchestrate VEGF signaling during developmental angiogenesis. Dev Cell, 2017, 42(5): 462-478.
31. Jiang X, Hu J, Wu Z, et al. Protein phosphatase 2A mediates YAP activation in endothelial cells upon VEGF stimulation and matrix stiffness. Front Cell Dev Biol, 2021, 9: 675562. doi: 10.3389/fcell.2021.675562.
32. Nakajima H, Yamamoto K, Agarwala S, et al. Flow-dependent endothelial YAP regulation contributes to vessel maintenance. Dev Cell, 2017, 40(6): 523-536.
33. Shen Y, Wang X, Lu J, et al. Reduction of liver metastasis stiffness improves response to bevacizumab in metastatic colorectal cancer. Cancer Cell, 2020, 37(6): 800-817.
34. Barreto S, Gonzalez-Vazquez A, Cameron AR, et al. Identification of the mechanisms by which age alters the mechanosensitivity of mesenchymal stromal cells on substrates of differing stiffness: Implications for osteogenesis and angiogenesis. Acta Biomater, 2017, 53: 59-69.
35. Xie J, Zhang D, Ling Y, et al. Substrate elasticity regulates vascular endothelial growth factor A (VEGFA) expression in adipose-derived stromal cells: Implications for potential angiogenesis. Colloids Surf B Biointerfaces, 2019, 175: 576-585.
36. Landau S, Ben-Shaul S, Levenberg S. Oscillatory train promotes vessel stabilization and alignment through fibroblast YAP-mediated mechanosensitivity. Adv Sci (Weinh), 2018, 5(9): 1800506. doi: 10.1002/advs.201800506.
37. Sack KD, Teran M, Nugent MA. Extracellular matrix stiffness controls VEGF signaling and processing in endothelial cells. J Cell Physiol, 2016, 231(9): 2026-2039.
38. Miller B, Sewell-Loftin MK. Mechanoregulation of vascular endothelial growth factor receptor 2 in angiogenesis. Front Cardiovasc Med, 2022, 8: 804934. doi: 10.3389/fcvm.2021.804934.
39. van der Stoel M, Schimmel L, Nawaz K, et al. DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis. J Cell Sci, 2020, 133(3): jcs239947. doi: 10.1242/jcs.239947.
40. Kai F, Laklai H, Weaver VM. Force matters: Biomechanical regulation of cell invasion and migration in disease. Trends Cell Biol, 2016, 26(7): 486-497.
41. Francis CR, Kincross H, Kushner EJ. Rab35 governs apicobasal polarity through regulation of actin dynamics during sprouting angiogenesis. Nat Commun, 2022, 13(1): 5276. doi: 10.1038/s41467-022-32853-5.

Chinese Journal of Reparative and Reconstructive Surgery

Research progress of matrix stiffness in regulating endothelial cell sprouting

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