It Takes Two to Tango: Endothelial TGFβ/BMP Signaling Crosstalk with Mechanobiology

Abstract

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGFβ) superfamily of cytokines. While some ligand members are potent inducers of angiogenesis, others promote vascular homeostasis. However, the precise understanding of the molecular mechanisms underlying these functions is still a growing research field. In bone, the tissue in which BMPs were first discovered, crosstalk of TGFβ/BMP signaling with mechanobiology is well understood. Likewise, the endothelium represents a tissue that is constantly exposed to multiple mechanical triggers, such as wall shear stress, elicited by blood flow or strain, and tension from the surrounding cells and to the extracellular matrix. To integrate mechanical stimuli, the cytoskeleton plays a pivotal role in the transduction of these forces in endothelial cells. Importantly, mechanical forces integrate on several levels of the TGFβ/BMP pathway, such as receptors and SMADs, but also global cell-architecture and nuclear chromatin re-organization. Here, we summarize the current literature on crosstalk mechanisms between biochemical cues elicited by TGFβ/BMP growth factors and mechanical cues, as shear stress or matrix stiffness that collectively orchestrate endothelial function. We focus on the different subcellular compartments in which the forces are sensed and integrated into the TGFβ/BMP growth factor signaling.

Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

“…In HHT, polymicrogyria appears exclusively associated with a subset of pathogenic variants in endoglin that is involved in blood flow-related mechano-transduction [74]. Taken together, these findings suggest that the interplay between the BMP9/endoglin/ALK1 pathway and blood flow-induced mechano-transduction signals plays a critical role during development of HHT lesions [64][65][66]72,73].…”

“…Also, it has been reported that defective fluid shear stress mechano-transduction mediates the formation of AVMs in HHT2 animal models [64,65]. The underlying mechanism appears to involve the BMP9/endoglin/ALK1/Smad4 pathway [66]. Thus, ALK1 expression requires blood flow [64], and fluid shear stress potentiates BMP9 activation of ALK1 signaling, which correlates with enhanced association of ALK1 and endoglin.…”

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

“…Focal adhesion-dependent tension modulates TGF-β signaling both negatively and positively [ 152 ]. Focal adhesions can negatively regulate TGF-β signaling by physically separating TβRI, which is found within focal adhesions, from TβRII, which is more commonly located around the edges, thus preventing formation of the functional TβRI/TβRII signaling complex [ 153 ].…”

“…Then, dysfunctional signaling downstream of focal adhesions would promote the upregulation of metalloproteinases and other matrix proteins, such as thrombospondin-1, which positively regulate AT 1 R and TGF-β signaling, further exacerbating ECM pathogenic remodeling [ 239 , 244 , 261 , 354 ]. Although the direct potentiation of TGF-β receptor activity by interference with myosin-driven focal adhesion maturation has been shown in vitro, it is not known whether it occurs in vivo [ 152 , 153 ].…”

Can Blood-Circulating Factors Unveil and Delay Your Biological Aging?

“…They regulate tissue morphogenesis in the embryo and are involved in several biological processes in adults, such as cell quiescence, apoptosis, differentiation, proliferation, and cell migration, especially playing a pivotal role in the regulation of hematopoiesis. Their abnormal expression is implicated in the pathogenesis of many diseases and aging [ 114 , 115 , 116 ].…”