Microvascular network growth and remodeling are common denominators for most age-related pathologies. For multiple pathologies (myocardial infarction, stroke, hypertension) promoting microvascular growth, termed angiogenesis, would be beneficial. For others (cancer, retinopathies, rheumatoid arthritis) blocking angiogenesis would be desirable. Most therapeutic strategies, however, are motivated based on studies using adult animal models. This approach is problematic and does not account for the impaired angiogenesis and the inherent network structure changes that might result from age. Considering the common conception that angiogenesis is impaired with age, a need exists to identify the causes and mechanisms of angiogenesis in aged scenarios, and for new tools to enable comparison of aged versus adult responses to therapy. The objective of this article will be to introduce opportunities for advancing our understanding of angiogenesis in aging through the discovery of novel cell changes along aged microvascular networks and the development of novel ex vivo models.

Kidney disease is an underappreciated public health crisis.Approximately 20% of all hospital admissions and more than half of all critically ill patients admitted to the intensive care units have acute kidney injury or AKI. 1 Further, 15% of the general population, or 1 in every 7 adults, have chronic kidney disease or CKD. 2 Kidney disease is the 9th leading cause of death and adds considerably to the cost of health care. In 2017 alone, Medicare spent $36 billion caring for patients with end-stage kidney disease on dialysis and an additional $84 billion on those with CKD. Although the kidneys are relatively small and account for only 1% of the total body weight, almost 20% of the blood flow is directed to the kidney under resting conditions. The resistance to blood flow within the renal microcirculation is intricately regulated by hormonal, paracrine, autocrine, and neural controls, to alter blood flow and glomerular filtration rate. Undoubtedly from a clinical perspective, understanding the structure and function of the renal microvasculature is important for

Pericytes are critical for microvascular stability and maintenance, among other important physiological functions, yet their involvement in vessel formation processes remains poorly understood. To gain insight into pericyte behaviors during vascular remodeling, we developed two complementary tissue explant models utilizing ‘double reporter’ animals with fluorescently-labeled pericytes and endothelial cells (via Ng2:DsRed and Flk-1:eGFP genes, respectively). Time-lapse confocal imaging of active vessel remodeling within adult connective tissues and embryonic skin revealed a subset of pericytes detaching and migrating away from the vessel wall. Vessel-associated pericytes displayed rapid filopodial sampling near sprouting endothelial cells that emerged from parent vessels to form nascent branches. Pericytes near angiogenic sprouts were also more migratory, initiating persistent and directional movement along newly forming vessels. Pericyte cell divisions coincided more frequently with elongating endothelial sprouts, rather than sprout initiation sites, an observation confirmed with in vivo data from the developing mouse brain. Taken together, these data suggest that (i) pericyte detachment from the vessel wall may represent an important physiological process to enhance endothelial cell plasticity during vascular remodeling, and (ii) pericyte migration and proliferation are highly synchronized with endothelial cell behaviors during the coordinated expansion of a vascular network.

Background: The development of models that incorporate intact microvascular networks enables the investigation of multicellular dynamics during angiogenesis. Our laboratory introduced the rat mesentery culture model as such a tool, which would be enhanced with mouse tissue. Since mouse mesentery is avascular, an alternative is mouse mesometrium, the connective tissue of uterine horns. The study’s objective was to demonstrate that mouse mesometrium contains microvascular networks that can be cultured to investigate multicellular dynamics during angiogenesis. Methods: Harvested mesometrium tissues from C57Bl/6 female mice were cultured in media with serum for up to 7 days. PECAM, NG2, αSMA, and LYVE-1 labeling identified endothelial cells, pericytes, smooth muscle cells, and lymphatic endothelial cells, respectively. Results: These cells comprised microvascular networks with arterioles, venules, and capillaries. Compared to day 0, capillary sprouts per vascular length were increased by 3 and 5 days in culture (day 0, 0.08 ± 0.01; day 3, 3.19 ± 0.78; day 5, 2.49 ± 0.05 sprouts/mm; p < 0.05). Time-lapse imaging of cultured tissues from FlkEGFP mice showcases the use of the model for lineage studies. The impact is supported by the identification of endothelial cell jumping from one sprout to another. Conclusion: These results introduce a novel culture model for investigating multicellular dynamics during angiogenesis in real-time ex vivo microvascular networks.

Using a multidimensional approach, we present evidence supporting that aged microvascular networks display vessel density and patterning similar to adult networks despite also being characterized by a decreased capacity to undergo angiogenesis. Thus, vessel loss is not necessarily a characteristic of aging.