Impaired vascular function in female Dentin matrix protein 1 null mice

Abstract

Dentin matrix protein 1 (DMP1) is highly expressed in mineralized tissues, especially in osteocytes. DMP1 is mainly involved in the control of mineralization and phosphate homeostasis. In humans mutations in DMP1 can lead to autosomal‐recessive hypophosphatemic rickets, which is due to increased production of fibroblast growth factor 23 (FGF23) by osteocytes. Interestingly, we found that aortic vascular smooth muscle expresses FGF receptor type 1 and the co‐receptors α and β‐klotho. DMP1 null mice have low bone mass and high circulating levels of FGF23, yet, cardiovascular function in these mice has not been examined. Therefore, we investigated the aortic vascular function in mature (16–25 week old) Dmp1−/− mice and wild‐type (WT) mice. Responses to ACh (10−4–10−9 M), SNP (10−4–10−9 M), PGF2α (10−4‐10−9 M), 5‐HT (10−5–10−9 M), and caffeine (10 mM) were examined by using isometric tension myography using normo‐phosphate buffers. Endothelium and smooth muscle dependent relaxations were unaltered in Dmp1−/− mice. There were, however, agonist and sex differences in the response to vasoconstrictors such that the contractile response to 5‐HT was selectively impaired (p=0.0013) in female Dmp1−/− mice versus male Dmp1−/− mice and WT mice of either sex. In addition, female Dmp1−/− mice exhibited weaker contractions to caffeine (p=0.02) indicating that SR calcium stores were reduced in these mice. Since the primary defect in Dmp1−/− mice is in the osteocytes it may be that bone releases a factor, possibly FGF23, which alters vascular function. This research was supported by NIH RC2 grant (ARO58962).