Thakkar, P. | Search bioRxiv

bioRxiv2024

Melanocortin system activates carotid body arterial chemoreceptors in hypertension

BackgroundThe bodys internal milieu is controlled by a system of interoceptors coupled to motor outflows that drive compensatory adaptive responses. These include the arterial chemoreceptors, best known for sensing arterial oxygen. In cardiometabolic diseases, such as essential hypertension, the carotid bodies (CB) exhibit heightened reflex sensitivity and tonic activity without an apparent stimulus. The mechanisms behind CB sensitization in these conditions are not well understood. MethodsGuided by functional genomics, a range of functional assays is used to interrogate downstream intracellular and interorgan signalling pathways involved in arterial chemosensory function. ResultsHere, we report the presence of the Melanocortin 4 receptor (MC4R) in the mammalian CB and show its elevated expression in experimental hypertension. We demonstrate that melanocortin agonists activate arterial chemosensory cells, modulating CB chemosensory afferent drive to influence both resting and chemoreflex-evoked sympathetic and ventilatory activity. Transcriptional analysis of hypertensive CB implicates the activation of the Mash1 (Ascl1) regulatory network in driving elevated Mc4r expression. ConclusionsCollectively, our data indicate a primarily pathophysiological role of melanocortin signalling in arterial chemosensation, contributing to excess sympathetic activity in cardiometabolic disease.

neuroscience↗

bioRxiv2020

A Whole Blood Thrombus Mimic: Constitutive Behavior Under Simple Shear

Deep vein thrombosis and pulmonary embolism affect 300,000-600,000 patients each year in the US. The progression from deep vein thrombus to pulmonary embolism occurs when blood clots, as a whole or partially, break off from the deep veins and eventually occlude the pulmonary arteries. Venous thromboembolism is the cause of up to 100,000 deaths per year in the US alone. To date, we dont fully understand this mechanical process among other reasons because in-vivo samples are difficult to obtain, highly heterogeneous, and their shapes are inappropriate for most mechanical tests. Toward overcoming these obstacles, we have set out to develop an in-vitro thrombus mimic and to test this mimic under large deformation simple shear. In addition to reporting on the mechanics of our mimics under simple shear, we explore the sensitivity of their mechanics to coagulation conditions and blood storage time, and compare three hyperelastic material models for their ability to fit our data. We found that thrombus mimics made from whole blood demonstrate strain-stiffening, a negative Poynting effect, and hysteresis when tested quasi-statically to 50% strain under simple shear. Additionally, we found that the stiffness of these mimics does not significantly vary with coagulation conditions or blood storage times. Of the three hyperelastic constitutive models that we tested, the Ogden model provided the best fits to both shear stress and normal stress. In conclusion, we developed a robust protocol to generate regularly-shaped, homogeneous thrombus mimics that lend themselves to simple shear testing under large deformation. Future studies will extend our model to include the effect of maturation and explore its fracture properties toward a better understanding of embolization.

bioengineering↗