Page 120 - Vitamin D and Cancer

5 Vitamin D and Angiogenesis 107

Some studies suggest that vitamin D insufficiency may contribute to the
pathogenesis of cardiovascular disease. Vascular calcification is a risk factor for
cardiovascular mortality. Almost all significant atherosclerotic lesions observed by
angiography are calcified [112]. In a study with two populations (173 subjects) at
high and moderate risk for coronary heart disease, serum levels of 1,25D are
3
inversely correlated with the extent of vascular calcification [113]. In contrast, the
extent of calcification is not correlated with the levels of osteocalcin or parathyroid
hormone [113]. Another study showed that serum levels of calcitriol are an indepen-
dent negative indicator of coronary calcium mass measured by electron-beam com-
puted tomography [114]. The protective role of 1,25D in vascular calcification and
3
atherosclerosis may be due to following mechanisms (reviewed in [104]). 1,25D
3
promotes the synthesis of the matrix Gla protein which inhibits vascular calcification.
Low serum level of calcitriol leads to increased level of PTH, which may promote
cardiovascular disease. 1,25D has been shown to inhibit the proliferation of VSMCs,
3
which express VDR. 1,25D also inhibits the production of the pro-inflammatory
3
cytokines TNF and IL-6 in monocytes. In a short-term supplementation study, vita-
min D and calcium result in increased serum 25(OH)D level, and reduce systolic
3 3
blood pressure, heart rate, and PTH levels in elderly women [115]. Vitamin D sup-
3
plementation reduces TNF serum levels while increases the levels of anti-inflamma-
tory cytokine interleukin 10 in a study on 93 chronic heart failure patients [116].
However, other studies have found 1,25D may contribute to the pathogenesis of
3
atherosclerotic lesions. 1,25D stimulates calcium influx (94) and VEGF expres-
3
sion in VSMCs [117]. 1,25D enhances vascular calcification in a dose-dependent
3
manner through increasing the expression of bone matrix protein osteopontin and
inhibiting the expression and secretion of PTH-related peptide (PTHrP) by VSMCs
[118]. Additionally, 1,25D induces VSMC migration in a dose-dependent manner
3
[100]. This effect is independent of gene transcription and involves non-genomic
activation of PI3K pathway [100].
In summary, there is growing evidence that vitamin D has an impact on vascula-
ture and angiogenesis. 1,25D has growth inhibitory effects in endothelial cells
3
through the induction of cell cycle arrest and apoptosis. 1,25D exerts anti-angiogenic
3
effects in a variety of tumor model systems in vivo. These observations provide addi-
tional preclinical rationale for the use of 1,25D in cancer therapy. 1,25D also regu-
3 3
lates vascular calcification and plays important roles in cardiovascular diseases.
Further investigations into the mechanisms of vitamin D anti-angiogenic effects will
be needed to enhance our understanding on its role in vasculature.

References

1. Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug
Discov 6:273–286
2. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660
3. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186
4. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395