Doctor of Philosophy, Indiana State University (2012)
Master of Science, Ball State University (2009)
Bachelor of Arts, Hanover College (2007)
Mary Red-Horse, Postdoctoral Faculty Sponsor
Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts.
Organogenesis during embryonic development occurs through the differentiation of progenitor cells. This process is extraordinarily accurate, but the mechanisms ensuring high fidelity are poorly understood. Coronary vessels of the mouse heart derive from at least two progenitor pools, the sinus venosus and endocardium. We find that the ELABELA (ELA)-APJ signaling axis is only required for sinus venosus-derived progenitors. Because they do not depend on ELA-APJ, endocardial progenitors are able to expand and compensate for faulty sinus venosus development in Apj mutants, leading to normal adult heart function. An upregulation of endocardial SOX17 accompanied compensation in Apj mutants, which was also seen in Ccbe1 knockouts, indicating that the endocardium is activated in multiple cases where sinus venosus angiogenesis is stunted. Our data demonstrate that by diversifying their responsivity to growth cues, distinct coronary progenitor pools are able to compensate for each other during coronary development, thereby providing robustness to organ development.
View details for DOI 10.1016/j.devcel.2017.08.008
View details for PubMedID 28890073
Coronary Artery Development: Progenitor Cells and Differentiation Pathways.
Annual Review of Physiology
View details for DOI 10.1146/annurev-physiol-022516-033953
Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects.
Science translational medicine
2017; 9 (407)
Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of Aplnr (Aplnr(ECKO) ) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the Apln(-/-) and Aplnr(ECKO) mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial Foxo1 deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the Apln(-/-) mice. The impaired glucose utilization in the Aplnr(ECKO) mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.
View details for DOI 10.1126/scitranslmed.aad4000
View details for PubMedID 28904225
Notch: A multi-functional integrating system of microenvironmental signals
2016; 418 (2): 227-241
The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact with their microenvironmental neighbors through direct cell-cell interactions, thereby directing a variety of developmental processes. Recent research is discovering that Notch signaling is also responsive to a broad variety of stimuli beyond cell-cell interactions, including: ECM composition, crosstalk with other signaling systems, shear stress, hypoxia, and hyperglycemia. Given this emerging understanding of Notch responsiveness to microenvironmental conditions, it appears that the classical view of Notch as a mechanism enabling cell-cell interactions, is only a part of a broader function to integrate microenvironmental cues. In this review, we summarize and discuss published data supporting the idea that the full function of Notch signaling is to serve as an integrator of microenvironmental signals thus allowing cells to sense and respond to a multitude of conditions around them.
View details for DOI 10.1016/j.ydbio.2016.08.023
View details for Web of Science ID 000384872900001
View details for PubMedID 27565024
- Letter by Papangeli et al Regarding Article, "The ERG-APLNR Axis Controls Pulmonary Venule Endothelial Proliferation in Pulmonary Veno-Occlusive Disease". Circulation 2015; 132 (2)
The sinus venosus contributes to coronary vasculature through VEGFC-stimulated angiogenesis.
2014; 141 (23): 4500-4512
Identifying coronary artery progenitors and their developmental pathways could inspire novel regenerative treatments for heart disease. Multiple sources of coronary vessels have been proposed, including the sinus venosus (SV), endocardium and proepicardium, but their relative contributions to the coronary circulation and the molecular mechanisms regulating their development are poorly understood. We created an ApjCreER mouse line as a lineage-tracing tool to map SV-derived vessels onto the heart and compared the resulting lineage pattern with endocardial and proepicardial contributions to the coronary circulation. The data showed a striking compartmentalization to coronary development. ApjCreER-traced vessels contributed to a large number of arteries, capillaries and veins on the dorsal and lateral sides of the heart. By contrast, untraced vessels predominated in the midline of the ventral aspect and ventricular septum, which are vessel populations primarily derived from the endocardium. The proepicardium gave rise to a smaller fraction of vessels spaced relatively uniformly throughout the ventricular walls. Dorsal (SV-derived) and ventral (endocardial-derived) coronary vessels developed in response to different growth signals. The absence of VEGFC, which is expressed in the epicardium, dramatically inhibited dorsal and lateral coronary growth but left vessels on the ventral side unaffected. We propose that complementary SV-derived and endocardial-derived migratory routes unite to form the coronary vasculature and that the former requires VEGFC, revealing its role as a tissue-specific mediator of blood endothelial development.
View details for DOI 10.1242/dev.113639
View details for PubMedID 25377552
View details for PubMedCentralID PMC4302936
Lumican exhibits anti-angiogenic activity in a context specific manner.
Cancer microenvironment : official journal of the International Cancer Microenvironment Society
2013; 6 (3): 263-271
A series of overexpression studies have shown that lumican suppresses angiogenesis in tumors produced from pancreatic adenocarcinoma, fibrosarcoma, and melanoma tumor cells. Despite lumican's anti-angiogenic activity, a clear correlation of differential expression of lumican in various cancers and cancer malignancy has failed to emerge. Therefore, we hypothesized that either 1.) endogenously expressed lumican is not anti-angiogenic or alternatively that 2.) lumican exhibits angiostatic activity only in limited microenvironments. Previously, lumican was shown to suppress tumor growth and angiogenesis in subcutaneously injected PanO2 pancreatic adenocarcinoma cells. Therefore, to determine if endogenously expressed lumican is anti-angiogenic we subcutaneously injected PanO2 cells into wild-type and lumican knockout mice and compared tumor growth and vascular densities of the resulting tumors. We found that tumors grown in lumican knockout animals were larger and contained significantly elevated vascular densities compared to those grown in wild-type mice. Interestingly however lumican knockout animals did not exhibit enhanced angiogenesis in aortic ring assays, matrigel plugs, or healing wound biopsies raising the possibility that lumican suppresses angiogenesis only in tumor microenvironments. To test this possibility, we sought a tumor model wherein lumican did not exhibit anti-angiogenic activity. Utilizing the 4T1 breast cancer model, we found that lumican suppressed 4T1 tumor growth and lung metastasis, but not angiogenesis. In conclusion, these results show that the angiostatic activity of lumican is dependent on currently undefined microenvironmental cues and therefore helps to understand why differential expression of lumican does not consistently correlate with human tumor malignancy.
View details for DOI 10.1007/s12307-013-0134-2
View details for PubMedID 23775523
Matrix Gla protein reinforces angiogenic resolution
2013; 85: 24-33
Matrix Gla Protein (MGP) is an ECM molecule commonly associated with dysfunctions of large blood vessels such as arteriosclerosis and atherosclerosis. However, the exact role of MGP in the microvasculature is not clear. Utilizing a mouse MGP knockout model we found that MGP suppresses angiogenic sprouting from mouse aorta restricts microvascular density in cardiac and skeletal muscle, and is an endogenous inhibitor of tumor angiogenesis. Similarly, morpholino based knockdown of MGP in zebrafish embryos caused a progressive loss of luminal structures in intersegmental vessels, a phenotype reminiscent of Dll4/Notch inhibition. Accordingly, MGP suppressed Notch-dependent Hes-1 promoter activity and expression of Jagged1 mRNA relative to Dll4 mRNA. However, inhibition of BMP but not Notch or VEGF signaling reversed the excessive angiogenic sprouting phenotype of MGP knockout aortic rings suggesting that MGP may normally suppress angiogenic sprouting by blocking BMP signaling. Collectively, these results suggest that MGP is a multi-functional inhibitor of normal and abnormal angiogenesis that may function by coordinating with both Notch and BMP signaling pathways.
View details for DOI 10.1016/j.mvr.2012.10.005
View details for Web of Science ID 000314318800004
View details for PubMedID 23110920