Biology subjects

Assoian, R. K.

Publications and source records attributed to Assoian, R. K..

3 recordsLinked to original sources

bioRxiv2023

Arterial mechanics, extracellular matrix, and smooth muscle differentiation in carotid arteries deficient for Rac1

Stiffening of the extracellular matrix (ECM) occurs after vascular injury and contributes to the injury-associated proliferation of vascular smooth muscle cells (SMCs). ECM stiffness also activates Rac-GTP, and SMC Rac1 deletion strongly reduces the proliferative response to injury in vivo. However, ECM stiffening and Rac can affect SMC differentiation, which, in itself, can influence ECM stiffness and proliferation. Here, we used pressure myography and immunofluorescence analysis of mouse carotid arteries to ask if the reported effect of Rac1 deletion on in vivo SMC proliferation might be secondary to a Rac effect on basal arterial stiffness or SMC differentiation. The results show that Rac1 deletion does not affect the abundance of arterial collagen-I, -III, or -V, the integrity of arterial elastin, or the arterial responses to pressure, including the axial and circumferential stretch-strain relationships that are assessments of arterial stiffness. Medial abundance of alpha-smooth muscle actin and smooth muscle-myosin heavy chain, markers of the SMC differentiated phenotype, were not statistically different in carotid arteries containing or deficient in Rac1. Nor did Rac1 deficiency have a statistically significant effect on carotid artery contraction to KCl. Overall, these data argue that the inhibitory effect of Rac1 deletion on in vivo SMC proliferation reflects a primary effect of Rac1 signaling to the cell cycle rather than a secondary effect associated with altered SMC differentiation or arterial stiffness.

cell biology↗

bioRxiv2022

Rac rather than Rho drives the early transcriptional response to extracellular matrix stiffness and mediates repression of ATF3

The Rho family GTPases, Rac and Rho, play critical roles in transmitting mechanical information contained within the extracellular matrix (ECM) to the cell. Rac and Rho have well described roles in regulating stiffness-dependent actin remodeling, proliferation and motility. However, much less is known about the relative roles of these GTPases in stiffness-dependent transcription, particularly at the genome-wide level. Here, we selectively inhibited Rac and Rho in mouse embryonic fibroblasts cultured on deformable substrata and used RNA sequencing to elucidate and compare the contribution of these GTPases to the early transcriptional response to ECM stiffness. Surprisingly, we found that Rac activation is almost exclusively responsible for the initial transcriptional response to ECM stiffness. We also identified Activating Transcription Factor 3 (ATF3) as a major target of stiffness/Rac signaling and show that ATF3 repression by ECM stiffness connects the stiffness-dependent activation of Rac to the induction of cyclin D1.

cell biology↗

bioRxiv2021

Efemp1 modulates elastic fiber formation and mechanics of the extrahepatic bile duct

EGF-Containing Fibulin Extracellular Matrix Protein 1 (EFEMP1, also called fibulin 3) is an extracellular matrix protein linked in a genome-wide association study to biliary atresia, a fibro-inflammatory disease of the neonatal extrahepatic bile duct. EFEMP1 is expressed in most tissues and Efemp1 null mice have decreased elastic fibers in visceral fascia; however, in contrast to other short fibulins (fibulins 4 and 5), EFEMP1 does not have a role in the development of large elastic fibers, and its overall function remains unclear. We demonstrated that EFEMP1 is expressed in the submucosa of both neonatal and adult mouse and human extrahepatic bile ducts and that, in adult Efemp1+/- mice, elastin organization into fibers is decreased. We used pressure myography, a technique developed to study the mechanics of the vasculature, to show that Efemp1+/- extrahepatic bile ducts are more compliant to luminal pressure, leading to increased circumferential stretch. We conclude that EFEMP1 has an important role in the formation of elastic fibers and mechanical properties of the extrahepatic bile duct. These data suggest that altered expression of EFEMP1 in the extrahepatic bile duct leads to an abnormal response to mechanical stress such as obstruction, potentially explaining the role of EFEMP1 in biliary atresia.

physiology↗