Vascular tone can also be regulated by an unknown ADRF which is released from perivascular adipose tissue. Soltis and Cassis [
111] first described that the presence of perivascular adipose tissue reduced vascular contractions by norepinephrine in rat aorta, which was later confirmed by Löhn
et al. [
6]. Also, isolated adipose tissue and cultured rat adipocytes relaxed precontracted rat aorta previously cleaned of adherent adipose tissue. This modulatory effect was attributed to ADRF, which functions as a regulator of arterial tone by active antagonism of contraction [
6]. A similar vasorelaxing effect of perivascular adipose tissue was observed in rat mesenteric arteries [
112], in mouse aorta [
113] and in human internal thoracic arteries [
114]. These data suggest a common pathway for arterial tone regulation in different species and different types of vascular structures. Verlohren
et al. [
112] even showed a positive correlation between the vasorelaxing influence of ADRF and the amount of perivascular adipose tissue. The observation that the resting membrane potential of vascular smooth muscle cells in arteries with adipose tissue is more hyperpolarized than in arteries without adipose tissue, further supports the idea that perivascular adipose tissue actively contributes to basal arterial tone [
112]. Whether NO formation and endothelium are involved in the vasorelaxation effect of ADRF is still a matter of debate [
6,
92,
112]. On the other hand, the vasorelaxing effect of ADRF is likely mediated by the opening of different K
+ channels in vascular smooth muscle cells, depending on the tissue and species studied [
6,
92,
112,
114,
115]. These divergent observations suggest a different distribution of K
+ channels in different vessels and/or species or the existence of different ADRFs.
More and more evidence is accumulating in support of the existence of different ADRFs. Löhn
et al. [
6] first suggested that ADRF is a protein. Furthermore, analyses of adipose tissue secretion in a recent electrophoresis study resulted in the visualization of different protein bands with different molecular masses (13.8 to 74.0 kDa), which may include ADRF [
116]. A possible candidate is peptide angiotensin [
1‐
7], which is a vasodilator located within adipose tissue surrounding rat aorta [
117]. Blocking this particular peptide inhibits the vasorelaxing effect of perivascular adipose tissue surrounding rat aorta [
117]. This hypothesis is contradicted, however, by the fact that certain ADRF-related potassium channels (K
ATP or K
v) [
6,
115] are not involved in this observed vasorelaxing effect. In addition to proteins, hydrogen peroxide produced from the NAD(P)H oxidase in adipocytes has been described as being involved in the endothelium-independent pathway of ADRF [
92]. Also hydrogen sulphide has been proposed as a novel candidate of ADRF or at least as a mediator in the ADRF effect [
115,
118], which is consistent with inactivation of ADRF by heating (65°C for 10 minutes) [
6]. Hydrogen sulphide has recently been described as a gasotransmitter generated by cystathionine γ-lyase (CSE) in perivascular adipose tissue [
119,
120]. Blocking of CSE inhibits the vasorelaxing effect of perivascular adipose tissue in rat aorta and mouse mesenteric arteries [
115,
118]. Moreover, hydrogen sulphide-induced vasorelaxation of rat aorta was inhibited by a particular ADRF-related potassium channel (KCNQ) blocker [
115]. However, hydrogen sulphide generation and CSE expression in the perivascular adipose tissue of stenotic aortas (but not in aortic tissue) have been shown to be increased in rat hypertension induced by abdominal aortic banding [
118], while the vasorelaxing effect of perivascular adipose tissue has been shown to be impaired in spontaneously hypertensive rats [
121]. This might indicate that ADRFs other than hydrogen sulphide are impaired, resulting in a reduced vasorelaxing effect of adipose tissue. On the other hand, it is difficult to compare both studies, as they used different models of hypertension. Furthermore, the upregulation of CSE and hydrogen sulphide generation in perivascular adipose tissue of stenotic aortas may have developed independently of hypertension, as CSE-knockout mice have been shown to be hypertensive [
120].
Obesity is characterized by a decrease in the vasorelaxing effect of perivascular adipose tissue, leading to hypertension [
22,
59,
91,
122]. This might imply a decrease in ADRF release or an imbalance in adipose tissue-derived relaxing and vasocontractile factors during obesity. On the other hand, hypoxia, which develops within adipose tissue during obesity [
12], has recently been shown to enhance the release of vasorelaxing factors released from adipose tissue, which might implicate ADRF [
123]. So, the release of ADRF in obesity warrants further research.