Margination decreases as the stenosis geometry becomes more gradual (eccentricity increases) with the exception of a sudden constriction/expansion geometry. Further, margination was found to increase with increasing percent occlusion and constriction length, likely a result of higher shear rate and longer residence time, respectively. Experimental results suggested that a constriction leads to an enhanced margination, whereas an expansion is responsible for a decrease in margination. A margination parameter, M, was used to quantify margination based on the particle distribution after velocity normalization. Spherical fluorescent particles with a diameter of 2.11 Ојm were suspended in blood and tracked as they moved into, through, and out of the constricted area. Microfluidic devices with a constricted area were fabricated to mimic a stenosed blood vessel with different extent of occlusion, constricted length, and eccentricity (gradualness of the constriction and expansion).

The current study investigated ten different geometries and their effects on margination. Margination refers to the movement of particles toward the blood vessel wall and is desirable for drug delivery. Recently, there has been an increased interest in shear-activated particle clusters for the treatment of stenosis, but there is a lack of literature investigating the impact of different stenosis geometries on particle margination. Stroke is a leading cause of death globally and is caused by stenoses, abnormal narrowings of blood vessels. We conclude that LKB1вЂ“AMPK-О±1 signaling pathways downstream of mitochondria are critical for the induction of HPV, in a manner also supported by AMPK-О±2 during severe hypoxia. However, deletion of AMPK-О±1, but not of AMPK-О±2, blocked hypoxia from inhibiting K V 1.5, the classical вЂњoxygen-sensingвЂќ K вЃє channel in pulmonary arterial myocytes. Fluorescence imaging of acutely isolated pulmonary arterial myocytes revealed that AMPK-О±1 or AMPK-О±2 deletion did not affect mitochondrial membrane potential during normoxia or hypoxia.

HPV was also attenuated by reduced expression of LKB1, a kinase that activates AMPK during energy stress, but not after deletion of CaMKK2, a kinase that activates AMPK in response to increases in cytoplasmic Ca ВІвЃє. By contrast, neither of these genetic manipulations affected serotonin-induced reductions in pulmonary vascular flow. Spectral Doppler ultrasound revealed that deletion of the AMPK-О±1 catalytic subunit blocked HPV in mice during mild (8% O 2 ) and severe (5% O 2 ) hypoxia, whereas AMPK-О±2 deletion attenuated HPV only during severe hypoxia. Contrary to this model, we have shown that the LKB1вЂ“AMPK-О±1 signaling pathway is critical to HPV. The unique sensitivity of these muscles to hypoxia is conferred by mitochondrial cytochrome c oxidase subunit 4 isoform 2, the inhibition of which has been proposed to trigger HPV through increased generation of mitochondrial reactive oxygen species. Hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching in the lungs, is triggered by mechanisms intrinsic to pulmonary arterial smooth muscles.

Constricting blood vessel meaning