Partial and Total Loss of Arterial Collagen XVIII Causes Atherosclerosis

Loss of Collagen XVIII Enhances Neovascularization and Vascular Permeability in Atherosclerosis

Some factions claim that loss of arterial collagen is causal to atherosclerosis without being very specific about the mechanism (where? the adventitia? the endothelial basement?  The media?  how? immune side?  smc autophagic?  oxidative?  proteolytic? autolysis?) and refer to studies done before regarding deranged hepatic metabolism of cholesterol during scurvy which causes a certain hyperlipidemia by bile metabolism deficiency and consequent lack of fecosteroid excretion.  Others will look at ratios of Collagens I, III, IV, and even V in the atherosclerotic plaque and their ratios during atherosclerosis.  However, the specific mechanism of collagen loss and atherosclerosis has never been scientifically described in a definitive study until this one.  Through simple logic, (common sense), it follows that singular or combinatory losses of the other arterial collagen subtypes would provide the same result experimentally, either in vitro or in vivo.

The Maeda paper showing that scurvy causes Evans Blue extravasation and gross damage to the arterial wall did not describe any atheromas, hyperplasias, or plaques because the mice die from scurvy before they can incur cumulative atherosclerosis.  They did prove that scurvy causes arterial degradation to the extent that lipoproteins and anything else can enter the artery that can't transgress a healthy, vitamin C (ascorbate) replete artery wall.

The implied connection between atherosclerosis and scurvy is collagen.  While ascorbate isn't the only vitamin involved in collagen synthesis, it is the only one that when absent will prevent proper polymerization of hydroxyl residues.  There is nothing to debate in this regard.  No ascorbate = no assembled collagen.  There may be pro-collagen formation and its strands, but they will never be assembled correctly into their "stronger than steel" fibers without vitamin C, but remain a useless stockpile of components.

It is important to note that the correct ratios of the various collagens is exceedingly important.  While much focus has been made on COL4 basement membranes in conferring tensile strength and resistance to metastasis, too much of COL4 without the other collagens in balance can cause mitochondrial death by integrin signaling abnormalities, as well as aberrant vitamin A processing.  It is not as simple as to say "the more collagen the better."  Not whatsoever is it that simple, and such a conclusion could be disastrous in clinic.  Fibrosis is a disorder of too much of the wrong collagen in the wrong place at the wrong time and is a devastating disorder. 

However, if the intrinsic collagens in the artery, such as COLXVIII, vanish, arteries become much more prone to lipid intrusion and the chain of events that occur after that.  As such, the normal constituency of arterial collagens, many of them not even recognized by conventional histopathology stains and immunohistochemistry, prevent large particle lipoprotein intrusion.  Collagen XVIII is a subtype that is virtually ignored in cardiology, yet possibly one of the most important subtypes.  It logically follows that deficiencies in the most commonly acknowledged collagens of the arterial media and basement membrane, COLI, COLIII, and COLIV, would cause similar problems of pathological permeability to both the clotting cascade biomolecules as well as the whole gamut of lipoproteins.  This deposition of foreign matter is understood for over five decades as being the causal moment of atherosclerosis, but it is still not widely accepted in 2015 that the collagenous and protein barrier of the artery built by vitamin C dependent enzymes is important to prevent this permeability event.