Abstract 19696: Blood Pressure Homeostasis and Renal Function Depends on Normal c-myb Activity in Bone Marrow-Derived Cells
Objective: We showed that the proto-oncogene c-myb regulates proliferation and differentiation of vascular smooth muscle cells (VSMCs) from specific adult vessel-resident progenitors and embryonic stem cells, however it was not known if c-Myb also regulates contractile function of VSMCs and integrated cardiovascular physiology.
Approach and Results: Mice homozygous for a hypomorphic c-myb allele with compromised c-Myb activity (hh) were compared to wild-type (WT). Hemodynamic assessments revealed decreased systolic (104±2 vs. 120±1 mmHg; P < 0.0001) and diastolic (71±2 vs. 83±1 mmHg; P < 0.001) blood pressure (BP) in hh compared to WT mice, which was confirmed by radiotelemetry in awake mice. Echocardiography found no differences in cardiac structure or function, and perfusion myography showed no defects in contractile function of hh arteries. Differences in plasma cytokines and biochemistry were observed. While plasma keratinocyte chemokine (KC) was elevated in hh mice, osmotic pump infusion of KC did not modulate BP. 24-h metabolic cage studies found increased urine output, altered creatinine clearance and fractional excretion of urea, suggesting altered renal function in hh mice. Flow cytometry revealed decreased renal B220+ B-cells in hh mice, with no differences in myeloid or T-cells. Since hh mice carry multiple hematological abnormalities, reciprocal bone marrow (BM) transplantation with WT and hh mice was performed. Reconstitution of WT mice with hh BM (hh>WT) decreased BP of WT recipients to hh levels; conversely WT>hh mice had BP equivalent to WT mice. Renal function of hh>WT mice also mirrored that of hh mice, including abnormalities in plasma and urine biochemistry. When challenged with DOCA-salt hypertension, hh mice had lower BP responses vs. WT mice.
Conclusions: The reduced c-Myb activity of hh mice does not alter their vessel contractile function or cardiac structure or function. BMT experiments demonstrate that low BP and altered renal function of hh mice is due to defective c-Myb activity in BM-derived cell populations. Renal flow cytometry suggests that B220+ B-cells may be implicated in this phenotype. Together, these data suggest that c-myb regulates BM-derived cell populations involved in kidney function and BP homeostasis.
Author Disclosures: E.A. Shikatani: None. A. Levy: None. R. Besla: None. A. Momen: None. H. Zhang: None. M. Chen: None. C. Simmons: None. P. Billia: None. C. Robbins: None. S. Heximer: None. J. Scholey: None. S. Bolz: None. M. Husain: None.
- © 2016 by American Heart Association, Inc.