Therapies aimed at manipulating the microcirculation require the ability to control angiogenesis, defined as the sprouting of new capillaries from existing vessels. In age-related pathologies (cancer, retinopathies, rheumatoid arthritis) blocking angiogenesis would be beneficial. In others (myocardial infarction, stroke, hypertension), promoting angiogenesis would be desirable. Most therapies are developed using adult animal models, yet this approach is problematic and does not account for the impaired angiogenesis and inherent changes resulting from age. Thus, new aging relevant models are required. The overall goal of this proposal is to provide novel information towards understanding impaired angiogenesis in aged tissues, while establishing an innovative ex vivo tissue culture model that enables real-time, mechanistic investigation in an intact aged microvascular network. No such model currently exists. Our laboratory has recently demonstrated that in cultured adult rat mesentery tissues, networks can be used to probe pericyte-endothelial cell interactions during. While pericytes are known to play a critical role in angiogenesis and are important targets for stem cell based therapies, surprisingly almost nothing is known about their function during aging. New preliminary data suggests two discoveries: that capillaries in aged networks have increased coverage of mature pericytes and that human aged bone marrow derived stem cells have increased pericyte fate versus adult cells. The proposed studies will leverage the capabilities of the rat mesentery culture model to test a novel overall hypothesis that increased mature pericyte coverage during aging is responsible for impaired angiogenesis. In doing so, our results will provide a new tool for mechanistic aging research and applied pre-clinical therapy evaluation.
Aim 1 : To test the hypothesis that NG2 mediated pericyte-endothelial cell interactions during angiogenesis are impaired in aged microvascular networks.
Aim 2 : To test the hypothesis that aged human bone marrow derived stem cells (BMSCs) display an increased pericyte fate during angiogenesis.
Aim 3 : To evaluate the effect of endothelial and pericyte targeted angiogenic drug therapies on aged microvascular networks. The proposed work will provide new information regarding altered pericyte function and stem cell fate during aging. These discoveries will introduce a new direction for aging research. The results will also demonstrate the usefulness of a new ex vivo model as a new tool.
Microvascular network remodeling is a common denominator for most age-related pathologies. Most therapies for these pathologies are developed using adult animal models, yet this approach is problematic and does not inherent changes resulting from age. This proposal will establish a new model for aging research that will enable investigators to better understand and manipulate aged microvascular networks.
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| Suarez-Martinez, Ariana D; Bierschenk, Susanne; Huang, Katie et al. (2018) A Novel ex vivo Mouse Mesometrium Culture Model for Investigating Angiogenesis in Microvascular Networks. J Vasc Res 55:125-135 |
| Sweat, Richard S; Sloas, David C; Stewart, Scott A et al. (2017) Aging is associated with impaired angiogenesis, but normal microvascular network structure, in the rat mesentery. Am J Physiol Heart Circ Physiol 312:H275-H284 |
| Motherwell, Jessica M; Azimi, Mohammad S; Spicer, Kristine et al. (2017) Evaluation of Arteriolar Smooth Muscle Cell Function in an Ex Vivo Microvascular Network Model. Sci Rep 7:2195 |
