Capillary malformations and other vascular malformations are the result of abnormal morphogenesis. Capillary malformations are characterized by ectatic papillary dermal capillaries and postcapillary venules in the upper reticular dermis, with some evidence of increased vessel density and no apparent proliferation of vessels. These ectatic vessels are lined by flat, benign-appearing endothelial cells, similar to the vessels of normal skin, with similar staining characteristics for endothelial antigens, including fibronectin, von Willebrand factor, and collagenous basement membrane proteins. The endothelial cells also exhibit cell turnover similar to normal vessels, supported by a paucity of mitoses or an uptake of tritiated thymidine. One study demonstrated a mean vessel depth of 0.46 mm in capillary malformations, suggesting that most of the vessels are superficial.

Evidence supports a neural role in both the development and progression of capillary malformations. Animal studies show that the sympathetic nervous system influences the composition and functional properties of the vessel wall during development.

Immunohistochemical studies of capillary malformations reveal a significantly decreased density of perivascular nervous tissue in lesional skin, suggesting that inadequate innervation may be in part responsible for decreased vascular tone and progressive vascular dilatation. Confocal microscopic studies demonstrate an inverse correlation between nerve density and blood vessel diameter and evidence that capillary malformations with the lowest nerve density exhibit the highest blood vessel density and the poorest response to laser intervention. The finding of increased vessel diameter and/or decreased nerve density may be secondary to other factors, such as local cytokine production or abnormal receptors; however, this has not been elucidated.

The potent endothelial cell mitogen vascular endothelial growth factor (VEGF)–A and its most active receptor VEGF-R2 expression are significantly increased in capillary malformation skin tissue compared with control skin. This may suggest that VEGF and VEGF-R could contribute to the pathogenesis of capillary malformations by inducing vessel proliferation and/or vasodilatation. If this is indeed a pathogenic factor, antiangiogenic treatments using VEGF blocking agents may prove to be useful for capillary malformations. Conversely, one report describes expansion of a biopsy-proven capillary malformation following partial surgical excision in an adult in whom the newly expanded capillary malformation expressed marked elevations of both tyrosine kinase receptor (Tie2) and its ligand angiopoietin-1 and no increase in VEGF. Tie2 and angiopoietin-1 are known regulators of vascular remodeling during angiogenesis, mutations of which have been demonstrated in familial venous malformations.

A somatic activating mutation encoding a p.Arg183Gln amino acid substitution in GNAQ, a q class of G-protein alpha subunits that mediates signals between G-protein–coupled receptors and their downstream effectors, has been shown to be the etiology of capillary malformations. This specific mutation was found in both lesional skin of nonsyndromic capillary malformations and in the lesional skin and affected brain tissue of patients with Sturge-Weber syndrome (SWS). Additionally, the endothelial cells of capillary malformations possess a higher density of the GNAQ mutation than other cells in the affected tissue. Other mutations in this G-protein have been identified in blue nevi, nevus of Ota, and in uveal melanoma. This helps explain the occurrence of both melanocytic nevi and capillary malformations co-localizing to the same area in phakomatosis pigmentovascularis. This G protein is in the MAP/MEK cell proliferation pathway. It has been posited that the timing of the mutation explains the tissue involvement and severity of the condition, with an earlier mutation occurring in SWS and a later one in nonsyndromic capillary malformations.

An inactivating mutation of RASA1 on 5q has been detected in some kindreds with multiple, small, round-to-oval, pink capillary malformations. RASA1 encodes a GTPase-activating protein, which negatively regulates Ras activity. These kindreds all had members who also had arteriovenous malformations (AVMs) or arteriovenous fistulae (AVFs). This disease has been coined capillary malformation-AVM syndrome to denote the 2 types of vascular malformations observed in these kindreds. One kindred with a novel RASA1 -inactivating mutation included a member with a large lower extremity capillary malformation with associated ipsilateral limb enlargement; however, another large kindred has been identified that has only capillary malformations and no evidence of AVMs or AVFs, suggesting that RASA1 mutations may be implicated more often than previously believed.