Diabetic vasculopathy, including macro and micro vascular disorders, is the leading cause of morbidity and mortality in patients with type 1 (T1) and type 2 (T2) diabetes mellitus (DM) [1]. A  lot  of  researches  pointed  out  that  endothelial  dysfunction,  characterized  by  an  imbalance  between  Endothelium-Derived  Relaxing  Factors  (EDRFs)  and  endothelium-derived   contracting   factors   (EDCFs)   play   a   central   role   on   the   development   and   progression of diabetic vasculopathy [2-5].

Endothelial   dysfunction   and   inflammation,   as   indicated   by   abnormal   flow-dependent  vasodilatation  and  by  increased  circulating  levels  of  adhesion  molecules  (ICAM-1 and E-selectin) are known to occur in T2DM and seems to be an important predictor in systemic atherogenesis [6]. Both  hyperglycemia  and  insulin  administration  increasing  circulating  levels  of  endothelin-1 (ET-1), an endothelial cell (EC)-derived potent vasoconstrictor peptide with mitogenic, pro-oxidative and pro-inflammatory properties that have shown to be extremely relevant to the pathophysiology of diabetic vasculopathy [7-10].Circulating  and  local  levels  of  ET-1  are  increased  in  diabetic  animal  models  and  diabetic patients [1,11,12]. Considering the global epidemic of diabetes, it seems to be critical to update our understanding  of  the  pathogenesis  of  diabetes  and  related  vascular  complications  in  order  to  clearly  understand  if  an  endothelial  protector  drug,  able  to  modulate  endothelial  adhesion  molecules  and  ET-1  could  represent  a  novel  treatment  options  for prevention and delaying the progression of diabetic complications [6].

The  mechanism  regulating  endothelial  cells  and  vascular  smooth  muscle  cells  function to become an important therapeutic targets in diabetic vascular complications and especially, the modulation of the vasoconstrictor, mitogenic, pro-oxidative and pro-inflammatory properties of ET-1 is undoubtedly important in diabetic complications. As  everybody  knows  the  small  vessels  (microcirculation  comprises  arterioles,  capillaries, venules and lymphatics, all <100 mm in diameter) are crucial for maintaining tissue  metabolism  and  structural  and  functional  changes  in  the  microcirculation  are present in diabetes mellitus irrespective of the organ studied (retina, kidney, CNS and skin)  [6]. The pathophysiology  of  diabetic  microangiopathy  is  complex  because  it  involves not only metabolic but also genetic factors [6]. For example has been shown that  subjects  with  diabetes  heredity  have  impaired  microvascular  responses  to  both  endothelium  and  nonendothelium-dependent  stimuli  in  the  skin  microcirculation  in  spite  of  normal  body  dimension,  normal  glucose  tolerance  and  normal  insulin  sensitivity  [13-15].  Early on  in  the  course  of  the  disease,  microvascular  perfusion 

occurs in the limbs, but most of the blood flow under normal thermal conditions passes through  arteriovenous  shunts,  bypassing  the  nutritive  capillary  bed  and  leading  the  so-called capillary ischemia [16,17].  Endothelial dysfunction, characterized by an imbalance between endothelium-derived  vasodilatator  and  vasoconstrictor  substances,  plays  an  important  role  in  the pathogenesis of vascular complications in diabetes, including microangiopathy. Almost   two   different   steps   seem   to   be   involved   in   the   microcirculation   imbalance:  leukocyte recruitment cascade and Endothelin-1 overexpression [16,18,19].

The recruitment of leukocytes from circulating blood into tissues is crucial for the inflammatory response: during this process a number of well-studied adhesion molecules on the endothelium sequentially interact with their ligands expressed on the cell surface of  leukocytes.  The  interaction  between  adhesion  molecules  and  ligands  occurs  in  a  cascade-like  fashion,  driving  leukocytes  from  the  circulation  to  the  extravascular  space,  that  is,  through  the  steps  of  leukocyte rolling, firm adhesion and transmigration (Figure 1) [20]. The selectin family of adhesion molecules mediates the capture and rolling  steps  of  leukocytes  along  the  endothelial  cells.  The  selectin  consists  of  three  members  of  C-type  lectins  (P,  E  and  L-selectin).

After  the  selectins  have  initiated  leukocyte  rolling  along  the  surface  of  endothelium,  a  different  set  of  adhesion  molecules  comes into play to reduce the leukocyte rolling velocity and allow to leukocyte to firmly adhere to the endothelial surface. This firm adhesion step is largely mediated by molecules of immunoglobulin superfamily  such  as  intercellular  adhesion  molecule  (ICAM  –  1) and  vascular  cell  adhesion  molecule  (VCAM-1)  expressed  by  endothelial cells and by those expressed constitutively by leukocyte or  by  many  other  types  of  cells.  Upon achievement  of  stable adhesion  to  the  endothelial  surface,  the  leukocyte  extravasate  between    endothelial    cells    along    the    intercellular    junctions. PECAM-1    (Platelet    Endothelial    Cell    Adhesion    Molecule)    and   VAP   (Vascular   Adhesion   Protein)   mediated   leukocytes   transmigration  [20].  Various  lines  of  evidence  indicate  that  the shedding  of  selectins  is  enhanced  on  the  endothelium  during  the  progression  of  diabetes  and  that  the  soluble  form  of  selectin  proteins has the potential to be a clinically useful biomarker of the severity  of  Diabetic  Rethinopathy:  E-Selectin,  in  particular,  may  also serve as a proangiogenic factor [20].

Once that the leukocytes have transmigrated from endothelial junctions  a  hyperproduction  of  ET-1  (Endothelin  1)  have  been  released  by  the  endotheliam.  ET-1  is  one  of  the  most  potent vasoconstrictor  described  and  has  been  suggested  to  be  involved  in  the  development  of  cardiovascular  disease.  It  possess  pro-inflammatory and profibrotic effects [6]. Enhanced of endogenous ET-1  has  been  demonstrated  in  hypertension,  coronary  artery  disease and heart failure [6]. In    diabetic    microangiopathy    one    important    feature    of    endothelial   dysfunction   is   an   increased   in   production   and   biological  activity  of  the  vasoactive  and  proinflammatory  peptide ET-1.  Elevated  levels  of  ET-1  are  found  in  patients  with  type  2  diabetes.  Furthermore  ET-1  may  contribute  to  the  development  of  endothelial  dysfunction,  and  consequently  insulin  resistance, by  increasing  the  production  of  Reactive  Oxigen  species,  mainly  superoxide anion, in the vasculature [6].

Figure 1: Leucocyte recruitment to the vessel wall

Taking into account the role of endothelial adhesion molecules (specifically  E-Selectin)  and  ET-1  in  the  pathogenesis  of  diabetic  microangiopathy  and  that  mostly  of  the  diabetic  complications such as retinopathy, nephropathy and neuropathy have their basis in  disturbed  microvascular  function,  we  hypnotized  that  added  to  standard therapy an endothelial protector drug, able to counteract hyperespression   of   endothelial   adhesion   molecules   and   ET-1  could be a new promising idea to postpone diabetic microvascular complication.

Recent  published  and  not  published  studies  shown  that  an  endothelial  protecting  drug,  such  as  aminapthone  (2-hydroxy-3-methyl-1,4-napthohydroquinone-2-p-aminobenzoate), a synthetic  molecules  derived  from  four  aminobenzoic  acid  which  is  currently  employed  for  capillary  disorders  could  be  useful  in  reverse   microalbuminuria   and   in   control   nailfold   periungueal  videocapillaroscopy     and     retinal     impairment     (OCT     and     fluoroangiography) in diabetic patients [21,22].

Considering    that    recently    aminapthone    shown    a    very    interesting  direct  pharmacodinamic  profile  on  endothelial  cells  (improvement  of  E-selectin  and  ET-1  hyperespression)  and  that other  drugs  like  avosentan  (a  new  potent,  non  peptidergic  and  selective   Et-a   receptor   antagonist)   demonstrated   to   decrease   proteinuria after 3 – 6 months of treatment, it seems encouraging to  study  if  this  new  endothelial  therapeutic  approach  could  be  useful for diabetic patients when added to standard therapy [23-29].

Since the typical approach with anti- ET-a selective antagonist avosertan,  atrasentan  and  sitaxsertan  seems  to  be  encouraging  in  term  of  efficacy  (proteinuria  control  in  diabetic  patients)  but  not in term of safety (increased of morbidity and mortality associated with anti-ET-a selective antagonists induced fluid retention) an old and  safe  endothelial  protector  approach  with  aminapthone  could represents a new/old way to postpone diabetic microangiopathy complications [27-29].

 References

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Keywords

Diabetes, Diabetic vasculopathy