Abstract
Simple SummaryThe formation of new blood vessels from already existing ones is a process of high clinical relevance, since it is of great importance for both physiological and pathological processes. In regard to tumors, the process is crucial, since it ensures the supply with nutrients and the growth of the tumor. The influence of mechanical factors on this biological process is an emerging field. Until now, the shear force of the blood flow has been considered the main mechanical parameter during angiogenesis. This review article provides an overview of further mechanical cues, with particular focus on the surrounding extracellular matrix impacting the cell behavior and, thus, regulating angiogenesis. This underlines the enormous importance of the mechanical properties of the extracellular matrix on cell biological processes and shows how changing the mechanics of the extracellular matrix could be used as a possible therapeutic approach in cancer therapy.Angiogenesis is of high clinical relevance as it plays a crucial role in physiological (e.g., tissue regeneration) and pathological processes (e.g., tumor growth). Besides chemical signals, such as VEGF, the relationship between cells and the extracellular matrix (ECM) can influence endothelial cell behavior during angiogenesis. Previously, in terms of the connection between angiogenesis and mechanical factors, researchers have focused on shear forces due to blood flow. However, it is becoming increasingly important to include the direct influence of the ECM on biological processes, such as angiogenesis. In this context, we focus on the stiffness of the surrounding ECM and the adhesion of cells to the ECM. Furthermore, we highlight the mechanical cues during the main stages of angiogenesis: cell migration, tip and stalk cells, and vessel stabilization. It becomes clear that the different stages of angiogenesis require various chemical and mechanical cues to be modulated by/modulate the stiffness of the ECM. Thus, changes of the ECM during tumor growth represent additional potential dysregulations of angiogenesis in addition to erroneous biochemical signals. This awareness could be the basis of therapeutic approaches to counteract specific processes in tumor angiogenesis.
Highlights
Sprouting angiogenesis is the formation of new blood vessels from pre-existing ones and plays a role in physiological processes, such as tissue regeneration, wound healing, embryonic development, and morphogenesis, as well as in pathological processes, such as tumor growth and metastasis [1,2,3]
Vascular endothelial growth factor (VEGF) further induces matrix degradation via urokinase-type plasminogen activator (uPA)/uPAR mediated proteolysis leading to collagen disposition in the extracellular matrix (ECM) and resulting in a stiffness increase [76,85,111]
This results in stiffness gradients and localized stiffening of the ECM, which is essential for the formation of new blood vessels
Summary
Sprouting angiogenesis is the formation of new blood vessels from pre-existing ones and plays a role in physiological processes, such as tissue regeneration, wound healing, embryonic development, and morphogenesis, as well as in pathological processes, such as tumor growth and metastasis [1,2,3]. The role of angiogenesis in tumor growth is important [1,3,5], which makes it one of the hallmarks of cancer [6]. EOnvnirtohnemoetnhter hand, tumo[9r,1d3e].vFeolrotpummoernbtioblyogiyts, estlifffcnaeusssreessualntiningcfrroemasteheinexsttriafcfenleluslsar[8m,1at3r]i.x F(EoCrMth) iiss orfegarseoant , tumor areasiimncsaptnoifrfbtnaeenscisde,.ebOnenctaitfiuhseeedoonbfeychhaarnonndii,nctcuirnmeflaoasrmedmdevasettilioofnfpnmoeresnfsitbccroaomnsibspe[a8sr,u1ep4d]p.toOortntehdthebeysouatrhnreoirnuihtnaiandldiinn, ctguremtaisosserue. On endothelial cells is of great importance This relates to tTumheoraaimngioofgetnheissisreavs iweewll iass ttoo pphryosvioidloegiacanl aonvgeirovgeienwesiso,fsihnocewdtifhfeeresntitfofnrgeasnssoaflstohe ECM affecsthsoewnddiofftehreenlitaslticfefnllesbserhanagveios.r, based on the essential steps of angiogenesis: cell migration,atffiepc/tTsshteeanladkiomtcheoelflliatshleicsleelrcletbvieioehnwa,viaisonrt,dobpavrseoesdvsiedolne stathnaeboeivslesizervnaitteiiawolnsot.fepThsohowef fatohnecguisotsgifelfinneeessssios:oncfettlhhl eemEiingCrflMau- ence of stiffnteiosns,;tfiopr/sttahlek ocevllesrevlieecwtiono,nanthdevaesrscehlistteacbtiulirzeatoiofnb. The listed stiffnesses of the references relate to in vitro experiments with endothelial cells. A tensioned network has an increased fiber stiffness. Incorporation of additional ECM proteins increases stiffness. Change of architecture increases tension and stiffness of the ECM network
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