Numerical evaluation reveals the effect of branching morphology on vessel transport properties during angiogenesis

Blood flow governs transport of oxygen and nutrients into tissues. Hypoxic tissues secrete VEGFs to promote angiogenesis during development and in tissue homeostasis. In contrast, tumors enhance pathologic angiogenesis during growth and metastasis, suggesting suppression of tumor angiogenesis could limit tumor growth. In line with these observations, various factors have been identified to control vessel formation in the last decades. However, their impact on the vascular transport properties of oxygen remain elusive. Here, we take a computational approach to examine the effects of vascular branching on blood flow in the growing vasculature. First of all, we reconstruct a 3D vascular model from the 2D confocal images of the growing vasculature at postnatal day 5 (P5) mouse retina, then simulate blood flow in the vasculatures, which are obtained from the gene targeting mouse models causing hypo- or hyper-branching vascular formation. Interestingly, hyper-branching morphology attenuates effective blood flow at the angiogenic front, likely promoting tissue hypoxia. In contrast, vascular hypo-branching enhances blood supply at the angiogenic front of the growing vasculature. Oxygen supply by newly formed blood vessels improves local hypoxia and decreases VEGF expression at the angiogenic front during angiogenesis. Consistent with the simulation results indicating improved blood flow in the hypo-branching vasculature, VEGF expression around the angiogenic front is reduced in those mouse retinas. Conversely, VEGF expression is enhanced in the angiogenic front of hyper-branching vasculature. Our results indicate the importance of detailed flow analysis in evaluating the vascular transport properties of branching morphology of the blood vessels.

Transport of Ketoprofen in Mammalian Blood Plasma

SummaryKetoprofen is a popular non-steroidal anti-inflammatory drug (NSAID) transported in the bloodstream mainly by serum albumin (SA). Ketoprofen is known to have multiple side effects and interactions with hundreds of other drugs, which might be related to its vascular transport by SA. Our work reveals that ketoprofen binds to a different subset of drug binding sites on human SA than has been observed for other species, despite the conservation of drug sites between species. We discuss potential reasons for the observed differences in the drug’s preferences for particular sites, including ketoprofen binding determinants in mammalian SAs and the effect of fatty acids on drug binding. The presented results show that the SA drug sites to which a particular drug binds cannot be easily predicted based only on a complex of SA from another species and the conservation of drug sites between species.

Numerical evaluation reveals the effect of branching morphology on vessel transport properties during angiogenesis

Blood flow governs transport of oxygen and nutrients into tissues. Hypoxic tissues secrete VEGFs to promote angiogenesis during development and in tissue homeostasis. In contrast, tumors enhance pathologic angiogenesis during growth and metastasis, suggesting suppression of tumor angiogenesis could limit tumor growth. In line with these observations, various factors have been identified to control vessel formation in the last decades. However, their impact on the vascular transport properties of oxygen remain elusive. Here, we take a computational approach to examine the effects of vascular branching on blood flow in the growing vasculature. First of all, we reconstruct the 3D vascular model from the 2D confocal images of the growing vasculature at P6 mouse retina, then simulate blood flow in the vasculature, which is applied for the gene targeting mouse models causing hypo- or hyper-branching vascular formation. Interestingly, hyper-branching morphology attenuates effective blood flow at the angiogenic front and promotes tissue hypoxia. In contrast, vascular hypo-branching enhances blood supply at the angiogenic front of the growing vasculature. Oxygen supply by newly formed blood vessels improves local hypoxia and decreases VEGF expression at the angiogenic front during angiogenesis. Consistent with the simulation results indicating improved blood flow in the hypo-branching vasculature, VEGF expression around the angiogenic front is reduced in those mouse retinas. Conversely, VEGF expression was enhanced in the hyper-branching vasculature in the mouse retina. Our results indicate the importance of detailed flow analysis in evaluating the vascular transport properties of branching morphology of the blood vessels.Author SummaryBlood vessels are important for the transport of various substances, such as oxygen, nutrients, and cells, to the entire body. Control of blood vessel formation is thought to be important in health and disease. In the last decades, various factors which regulate blood vessel branching morphology have been identified. Gene modification of some of these identified factors results in hyper-branching of the vasculature while others cause hypo-branching of the vessel. Given the importance of the transport property of the blood vessel, it is important to examine the effect of these identified factors on the transport property of the affected vascular morphology. In line with these facts, we reconstruct 3D vessel structures from 2D confocal microscopy images. We then simulate blood flow in the structures numerically. Interestingly, our results suggest vessel network complexity negatively affects the blood perfusion efficiency and tissue oxygenation during angiogenesis. Thus, our results highlight the importance of flow analysis considering the detailed 3D branching pattern of the vascular network to quantitatively evaluate its transport properties.

Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy

Dexamethasone, a widely used corticosteroid, has recently been reported as the first drug to increase the survival chances of patients with severe COVID-19. Therapeutic agents, including dexamethasone, are mostly transported through the body by binding to serum albumin. Here, the first structure of serum albumin in complex with dexamethasone is reported. Dexamethasone binds to drug site 7, which is also the binding site for commonly used nonsteroidal anti-inflammatory drugs and testosterone, suggesting potentially problematic binding competition. This study bridges structural findings with an analysis of publicly available clinical data from Wuhan and suggests that an adjustment of the dexamethasone regimen should be further investigated as a strategy for patients affected by two major COVID-19 risk factors: low albumin levels and diabetes.

Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy

Dexamethasone, a widely used corticosteroid, has recently been reported as the first drug to increase the survival chances of patients with severe COVID-19. Therapeutic agents, including dexamethasone, are mostly transported through the body by binding to serum albumin. Herein, we report the first structure of serum albumin in complex with dexamethasone. We show that it binds to Drug Site 7, which is also the binding site for commonly used nonsteroidal anti-inflammatory drugs and testosterone, suggesting potentially problematic binding competition. This study bridges structural findings with our analysis of publicly available clinical data from Wuhan and suggests that an adjustment of dexamethasone regimen should be considered for patients affected by two major COVID-19 risk-factors: low albumin levels and diabetes.One Sentence SummaryStructure of serum albumin with dexamethasone reveals why the drug may not always help COVID-19 patients.

Engineering nanoparticles to tackle tumor barriers

Engineering strategies of nanoparticles were elaborated to overcome delivery barriers from the perspectives of trans-vascular transport and interstitial transport.