Vascular disease, the greatest single cause of morbidity and mortality in developed societies, results from interactions between circulating inflammatory cells, the endothelium that lines the vasculature, underlying vascular smooth muscle cells (VSMCs) that comprise most of the arterial wall, and stem/progenitor cells found in the surrounding adventitia. The underlying pathogenesis is complex: factors that impinge on these cell types include reactivated developmental pathways, innate and acquired immune responses, and changes in cell function that result from physical stresses, perturbed blood flow, and biochemical stimuli. Our general approach is to characterize these responses at the molecular level, in cultured cells, and in mouse models that reflect specific types of vascular injury, including atherosclerosis, mechanical trauma, and transplant-associated arteriosclerosis.

Fat proteins are important regulators of cell growth and planar cell polarity. We have linked the atypical cadherin adhesion molecule Fat1 to significant effects on mammalian vascular remodeling. Our studies in VSMCs show that Fat1 interacts with beta-catenin to limit canonical Wnt signaling, a core developmental pathway that regulates many aspects of metazoan embryogenesis, and with Atrophin proteins to control VSMC directional migration. Recent findings suggest that Fat1 is an important regulator of VSMC growth and differentiation in injured vessels, and ongoing studies aim to understand the intracellular and extracellular signals that emanate from Fat1 in cis- and trans-signaling modes. Direct studies of beta-catenin indicate that its expression in VSMCs is required for vascular formation in development and important in adult arterial injury response. Efforts to understand beta-catenin’s essential function in these settings are underway.

Diabetes and obesity are important risk factors for cardiovascular disease. We are investigating how allograft inflammatory factor-1 (Aif-1), a 17 kD Ca2+-binding protein contributes to these conditions. Specific Aif-1 isoform-dependent functions that underlie effects on macrophage migration, phagocytosis, survival, and inflammatory signaling are subjects of ongoing studies. Finally, in collaboration with Richard Stanley, we have characterized a role for colony stimulating factor-1 (CSF-1), the main regulator of macrophage survival, proliferation, and differentiation, in control of transplant-associated arteriosclerosis, the major barrier to long-term success of organ transplants. Surprisingly, this effect appears to involve VSMC-associated CSF-1 in an autocrine/juxtacrine mechanism that is largely independent of macrophages.

Ongoing work in these areas involves defining the molecular bases for these observations. By identifying such novel mechanisms, we hope to find new targets for therapeutic intervention to improve vascular disease prevention and treatment.

1.     Riascos-Bernal D, Chinnasamy P, Cao L, Dunaway CM, Valenta T, Basler K, Sibinga, NES. β-Catenin C-terminal signals suppress p53 and are essential for artery formation. Nature Communications, 2016 Aug 8;7:12389. PMID: 27499244

2.     Cao L, Riascos-Bernal D, Chinnasamy P, Dunaway C, Pujato M, Fiser A, Sibinga NES. Control of mitochondrial function and cell growth by the atypical cadherin Fat1. Nature, 2016 Nov 9;539(7630):575-578. PMID: 27828948.

3.     Riascos-Bernal DF, Chinnasamy P, Gross JN, Almonte V, Egaña-Gorroño L, Parikh D, Jayakumar S, Guo L, Sibinga NES. Inhibition of smooth muscle β-catenin hinders neointima formation after vascular injury. Arterioscler Thromb Vasc Biol, 2017 May;37(5):879-888. PMID: 28302627.

4.     Egaña-Gorroño L, Chinnasamy P, Casimiro I, Almonte VM, Parikh D, Oliveira-Paula GH, Jayakumar S, Law C, Riascos-Bernal DF, Sibinga NES. Allograft Inflammatory Factor-1 Supports Macrophage Survival and Efferocytosis and Limits Necrosis in Atherosclerotic Plaques. Atherosclerosis, 2019 Oct;289:184-194. PMID: 31439353.

5.     Becher T, Riascos-Bernal DF, Kramer DJ, Almonte VM, Chi J, Tong T, Oliveira-Paula GH, Koleilat I, Chen W, Cohen P, Sibinga NES. Three-Dimensional Imaging Provides Detailed Atherosclerotic Plaque Morphology and Reveals Angiogenesis after Carotid Artery Ligation. Circ Res. 2020 Feb 28;126(5):619-632. PMID: 31914850. PMCID: PMC7047629.

6.     Parikh D, Riascos-Bernal DF, Egaña-Gorroño L, Jayakumar S, Almonte V, Chinnasamy P, Sibinga NES. Allograft inflammatory factor-1-like is not essential for age dependent weight gain or HFD-induced obesity and glucose insensitivity. Sci Rep. 2020 Feb 27;10(1):3594. PMID: 32107417. PMCID: PMC7046694.

7.     Chen W, Fitzpatrick J, Sozio SM, Jaar BG, Estrella MM, Riascos-Bernal DF, Wu TT, Qiu Y, Kurland IJ, Dubin RF, Chen Y, Parekh RS, Bushinsky DA, Sibinga NES. Identification of Novel Biomarkers and Pathways for Coronary Artery Calcification in Nondiabetic Patients on Hemodialysis Using Metabolomic Profiling. Kidney360. 2021 February;2(2):279-289. PubMed PMID: 34723191; PubMed Central PMCID: PMC8553022; DOI: 10.34067/kid.0004422020.

8.     Almonte VM, Uriyanghai U, Egaña-Gorroño L, Parikh D, Oliveira-Paula GH, Zhang J, Jayakumar S, Riascos-Bernal DF, Sibinga NES. PLX3397, a CSF1 receptor inhibitor, limits allotransplantation-induced vascular remodeling. Cardiovasc Res. 2021 Sep 3:cvab289. doi: 10.1093/cvr/cvab289. Online ahead of print. PMID: 34478521.

9.     Lituma PJ, Woo E, O’Hara BF, Castillo PE, Sibinga NES, Nandi S. Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1. Proc Nat Acad Sci U S A. 2021, Nov 16;118(46):e2115539118.  doi: 10.1073/pnas.2115539118. PMID: 34764226. PMCID: PMC8609554.

10.  Riascos-Bernal DF, Maira A, Sibinga NES. The Atypical Cadherin FAT1 Limits Mitochondrial Respiration and Proliferation of Vascular Smooth Muscle Cells. Front Cardiovasc Med. 2022 May 11;9:905717. doi: 10.3389/fcvm.2022.905717. PMID: 35647082

11.  Parikh D, Jayakumar S, Oliveira-Paula GH, Almonte V, Riascos-Bernal DF, Sibinga NES. Allograft inflammatory factor-1-like is a situational regulator of leptin levels, hyperphagia, and obesity. iScience. 2022 Sep 3;25(10):105058. doi: 10.1016/j.isci.2022.105058. eCollection 2022 Oct 21. PMID: 36134334